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Therapeutic potential of CDK4/6 inhibitors in renal cell carcinoma

Nature Reviews Urology volume 19, pages 305–320 (2022)Cite this article

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Abstract

The treatment of advanced and metastatic kidney cancer has entered a golden era with the addition of more therapeutic options, improved survival and new targeted therapies. Tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and immune checkpoint blockade have all been shown to be promising strategies in the treatment of renal cell carcinoma (RCC). However, little is known about the best therapeutic approach for individual patients with RCC and how to combat therapeutic resistance. Cancers, including RCC, rely on sustained replicative potential. The cyclin-dependent kinases CDK4 and CDK6 are involved in cell-cycle regulation with additional roles in metabolism, immunogenicity and antitumour immune response. Inhibitors of CDK4 and CDK6 are now commonly used as approved and investigative treatments in breast cancer, as well as several other tumours. Furthermore, CDK4/6 inhibitors have been shown to work synergistically with other kinase inhibitors, including mTOR inhibitors, as well as with immune checkpoint inhibitors in preclinical cancer models. The effect of CDK4/6 inhibitors in kidney cancer is relatively understudied compared with other cancers, but the preclinical studies available are promising. Collectively, growing evidence suggests that targeting CDK4 and CDK6 in kidney cancer, alone and in combination with current therapeutics including mTOR and immune checkpoint inhibitors, might have therapeutic benefit and should be further explored.

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Fig. 1: CDK4 stabilization and canonical function in the cell cycle.
Fig. 2: Cellular functions and regulation of CDK4.
Fig. 3: Structure of CDK6 in complex with CDK4/6 inhibitors.
Fig. 4: Timeline of CDK4/6 inhibitor development and approval of systemic therapies for renal cell carcinoma.
Fig. 5: CDK4 at the interface between mTOR signalling and immune checkpoint regulation.

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References

  1. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020).

    Article  PubMed  Google Scholar 

  2. Hsieh, F. S. et al. Palbociclib induces activation of AMPK and inhibits hepatocellular carcinoma in a CDK4/6-independent manner. Mol. Oncol. 11, 1035–1049 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. McDermott, D. F. et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 23, 133–141 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Motzer, R. J. et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372, 449–456 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Motzer, R. J. et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 356, 115–124 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Shen, C. & Kaelin, W. G. Jr The VHL/HIF axis in clear cell renal carcinoma. Semin. Cancer Biol. 23, 18–25 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Linehan, W. M. et al. The metabolic basis of kidney cancer. Cancer Discov. 9, 1006–1021 (2019).

    Article  CAS  PubMed  Google Scholar 

  8. Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Turner, N. C. et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 373, 209–219 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Hortobagyi, G. N. et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N. Engl. J. Med. 375, 1738–1748 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. Sledge, G. W. Jr et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J. Clin. Oncol. 35, 2875–2884 (2017).

    Article  CAS  PubMed  Google Scholar 

  15. Baker, S. J. & Reddy, E. P. CDK4: a key player in the cell cycle, development, and cancer. Genes Cancer 3, 658–669 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Schopf, F. H., Biebl, M. M. & Buchner, J. The HSP90 chaperone machinery. Nat. Rev. Mol. Cell Biol. 18, 345–360 (2017).

    Article  CAS  PubMed  Google Scholar 

  17. Bai, J., Li, Y. & Zhang, G. Cell cycle regulation and anticancer drug discovery. Cancer Biol. Med. 14, 348–362 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Knudsen, E. S. & Witkiewicz, A. K. The strange case of CDK4/6 inhibitors: mechanisms, resistance, and combination strategies. Trends Cancer 3, 39–55 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pernas, S., Tolaney, S. M., Winer, E. P. & Goel, S. CDK4/6 inhibition in breast cancer: current practice and future directions. Ther. Adv. Med. Oncol. 10, 1758835918786451 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. O’Leary, B., Finn, R. S. & Turner, N. C. Treating cancer with selective CDK4/6 inhibitors. Nat. Rev. Clin. Oncol. 13, 417–430 (2016).

    Article  PubMed  CAS  Google Scholar 

  21. Finn, R. S. et al. Palbociclib and letrozole in advanced breast cancer. N. Engl. J. Med. 375, 1925–1936 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Yardley, D. A. MONALEESA clinical program: a review of ribociclib use in different clinical settings. Future Oncol. 15, 2673–2686 (2019).

    Article  CAS  PubMed  Google Scholar 

  23. Klein, M. E., Kovatcheva, M., Davis, L. E., Tap, W. D. & Koff, A. CDK4/6 inhibitors: the mechanism of action may not be as simple as once thought. Cancer Cell 34, 9–20 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04751929 (2021).

  25. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04438824 (2021).

  26. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04360941 (2021).

  27. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04213404 (2021).

  28. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03294694 (2020).

  29. Cretella, D. et al. The anti-tumor efficacy of CDK4/6 inhibition is enhanced by the combination with PI3K/AKT/mTOR inhibitors through impairment of glucose metabolism in TNBC cells. J. Exp. Clin. Cancer Res. 37, 72 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Gopalan, P. K. et al. CDK4/6 inhibition stabilizes disease in patients with p16-null non-small cell lung cancer and is synergistic with mTOR inhibition. Oncotarget 9, 37352–37366 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Michaloglou, C. et al. Combined inhibition of mTOR and CDK4/6 is required for optimal blockade of E2F function and long-term growth inhibition in estrogen receptor-positive breast cancer. Mol. Cancer Ther. 17, 908–920 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yamamoto, T., Kanaya, N., Somlo, G. & Chen, S. Synergistic anti-cancer activity of CDK4/6 inhibitor palbociclib and dual mTOR kinase inhibitor MLN0128 in pRb-expressing ER-negative breast cancer. Breast Cancer Res. Treat. 174, 615–625 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Song, X. et al. Combined CDK4/6 and Pan-mTOR inhibition is synergistic against intrahepatic cholangiocarcinoma. Clin. Cancer Res. 25, 403–413 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Olmez, I. et al. Combined CDK4/6 and mTOR inhibition is synergistic against glioblastoma via multiple mechanisms. Clin. Cancer Res. 23, 6958–6968 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Asby, D. J. et al. Combined use of CDK4/6 and mTOR inhibitors induce synergistic growth arrest of diffuse intrinsic pontine glioma cells via mutual downregulation of mTORC1 activity. Cancer Manag. Res. 10, 3483–3500 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Goel, S. et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature 548, 471–475 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Deng, J. et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov. 8, 216–233 (2018).

    Article  CAS  PubMed  Google Scholar 

  38. Schaer, D. A. et al. The CDK4/6 inhibitor abemaciclib induces a T cell inflamed tumor microenvironment and enhances the efficacy of PD-L1 checkpoint blockade. Cell Rep. 22, 2978–2994 (2018).

    Article  CAS  PubMed  Google Scholar 

  39. Yu, J. et al. Genetic aberrations in the CDK4 pathway are associated with innate resistance to PD-1 blockade in Chinese patients with non-cutaneous melanoma. Clin. Cancer Res. 25, 6511–6523 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. Zhang, J. et al. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 553, 91–95 (2018).

    Article  CAS  PubMed  Google Scholar 

  41. Malumbres, M. & Barbacid, M. Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer 9, 153–166 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Satyanarayana, A. & Kaldis, P. Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms. Oncogene 28, 2925–2939 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Sherr, C. J. D-type cyclins. Trends Biochem. Sci. 20, 187–190 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Sherr, C. J. & Roberts, J. M. Living with or without cyclins and cyclin-dependent kinases. Genes Dev. 18, 2699–2711 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Malumbres, M. et al. Mammalian cells cycle without the D-type cyclin-dependent kinases CDK4 and CDK6. Cell 118, 493–504 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Rane, S. G. et al. Loss of CDK4 expression causes insulin-deficient diabetes and CDK4 activation results in beta-islet cell hyperplasia. Nat. Genet. 22, 44–52 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Kato, J., Matsushime, H., Hiebert, S. W., Ewen, M. E. & Sherr, C. J. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev. 7, 331–342 (1993).

    Article  CAS  PubMed  Google Scholar 

  48. Pan, W., Cox, S., Hoess, R. H. & Grafstrom, R. H. A cyclin D1/cyclin-dependent kinase 4 binding site within the C domain of the retinoblastoma protein. Cancer Res. 61, 2885–2891 (2001).

    CAS  PubMed  Google Scholar 

  49. Wallace, M. & Ball, K. L. Docking-dependent regulation of the Rb tumor suppressor protein by Cdk4. Mol. Cell Biol. 24, 5606–5619 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Braden, W. A., McClendon, A. K. & Knudsen, E. S. Cyclin-dependent kinase 4/6 activity is a critical determinant of pre-replication complex assembly. Oncogene 27, 7083–7093 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Ruas, M. et al. CDK4 and CDK6 delay senescence by kinase-dependent and p16INK4a-independent mechanisms. Mol. Cell Biol. 27, 4273–4282 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Brookes, S. et al. Evidence for a CDK4-dependent checkpoint in a conditional model of cellular senescence. Cell Cycle 14, 1164–1173 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Matthews, H. K., Bertoli, C. & de Bruin, R. A. M. Cell cycle control in cancer. Nat. Rev. Mol. Cell Biol. 23, 74–88 (2021).

    Article  PubMed  CAS  Google Scholar 

  54. Haas, K. et al. Mutual requirement of CDK4 and Myc in malignant transformation: evidence for cyclin D1/CDK4 and p16INK4A as upstream regulators of Myc. Oncogene 15, 179–192 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Hermeking, H. et al. Identification of CDK4 as a target of c-MYC. Proc. Natl Acad. Sci. USA 97, 2229–2234 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Obaya, A. J., Kotenko, I., Cole, M. D. & Sedivy, J. M. The proto-oncogene c-myc acts through the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 to facilitate the activation of CDK4 and CDK6 and early G1 phase progression. J. Biol. Chem. 277, 31263–31269 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Tsutsui, T. et al. Targeted disruption of CDK4 delays cell cycle entry with enhanced p27(Kip1) activity. Mol. Cell Biol. 19, 7011–7019 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Meyer, C. A. et al. Drosophila CDK4 is required for normal growth and is dispensable for cell cycle progression. EMBO J. 19, 4533–4542 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Jaakkola, P. et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Frei, C. & Edgar, B. A. Drosophila cyclin D/Cdk4 requires Hif-1 prolyl hydroxylase to drive cell growth. Dev. Cell 6, 241–251 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Lee, Y. et al. Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression. Nature 510, 547–551 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wang, H. et al. The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival. Nature 546, 426–430 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Romero-Pozuelo, J., Figlia, G., Kaya, O., Martin-Villalba, A. & Teleman, A. A. CDK4 and CDK6 couple the cell-cycle machinery to cell growth via mTORC1. Cell Rep. 31, 107504 (2020).

    Article  CAS  PubMed  Google Scholar 

  64. Krall, A. S. & Christofk, H. R. Cell cycle: division enzyme regulates metabolism. Nature 546, 357–358 (2017).

    Article  CAS  PubMed  Google Scholar 

  65. Serrano, M., Hannon, G. J. & Beach, D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704–707 (1993).

    Article  CAS  PubMed  Google Scholar 

  66. Annicotte, J. S. et al. The CDK4-pRB-E2F1 pathway controls insulin secretion. Nat. Cell Biol. 11, 1017–1023 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Martinez-Carreres, L. et al. CDK4 regulates lysosomal function and mTORC1 activation to promote cancer cell survival. Cancer Res. 79, 5245–5259 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hardie, D. G., Ross, F. A. & Hawley, S. A. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251–262 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lopez-Mejia, I. C. et al. CDK4 phosphorylates AMPKalpha2 to inhibit its activity and repress fatty acid oxidation. Mol. Cell 68, 336–349.e6 (2017).

    Article  CAS  PubMed  Google Scholar 

  70. Nebenfuehr, S., Kollmann, K. & Sexl, V. The role of CDK6 in cancer. Int. J. Cancer 147, 2988–2995 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Dai, K., Kobayashi, R. & Beach, D. Physical interaction of mammalian CDC37 with CDK4. J. Biol. Chem. 271, 22030–22034 (1996).

    Article  CAS  PubMed  Google Scholar 

  72. Stepanova, L., Leng, X., Parker, S. B. & Harper, J. W. Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes Dev. 10, 1491–1502 (1996).

    Article  CAS  PubMed  Google Scholar 

  73. Gu, Y., Turck, C. W. & Morgan, D. O. Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature 366, 707–710 (1993).

    Article  CAS  PubMed  Google Scholar 

  74. Harper, J. W., Adami, G. R., Wei, N., Keyomarsi, K. & Elledge, S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75, 805–816 (1993).

    Article  CAS  PubMed  Google Scholar 

  75. Xiong, Y. et al. p21 is a universal inhibitor of cyclin kinases. Nature 366, 701–704 (1993).

    Article  CAS  PubMed  Google Scholar 

  76. Noda, A., Ning, Y., Venable, S. F., Pereira-Smith, O. M. & Smith, J. R. Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp. Cell Res. 211, 90–98 (1994).

    Article  CAS  PubMed  Google Scholar 

  77. Polyak, K. et al. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 8, 9–22 (1994).

    Article  CAS  PubMed  Google Scholar 

  78. Polyak, K. et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78, 59–66 (1994).

    Article  CAS  PubMed  Google Scholar 

  79. Toyoshima, H. & Hunter, T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78, 67–74 (1994).

    Article  CAS  PubMed  Google Scholar 

  80. Lee, M. H., Reynisdottir, I. & Massague, J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev. 9, 639–649 (1995).

    Article  CAS  PubMed  Google Scholar 

  81. Matsuoka, S. et al. p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev. 9, 650–662 (1995).

    Article  CAS  PubMed  Google Scholar 

  82. Hannon, G. J. & Beach, D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371, 257–261 (1994).

    Article  CAS  PubMed  Google Scholar 

  83. Guan, K. L. et al. Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev. 8, 2939–2952 (1994).

    Article  CAS  PubMed  Google Scholar 

  84. Hirai, H., Roussel, M. F., Kato, J. Y., Ashmun, R. A. & Sherr, C. J. Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Mol. Cell Biol. 15, 2672–2681 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chan, F. K., Zhang, J., Cheng, L., Shapiro, D. N. & Winoto, A. Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4. Mol. Cell Biol. 15, 2682–2688 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. LaBaer, J. et al. New functional activities for the p21 family of CDK inhibitors. Genes Dev. 11, 847–862 (1997).

    Article  CAS  PubMed  Google Scholar 

  87. James, M. K., Ray, A., Leznova, D. & Blain, S. W. Differential modification of p27Kip1 controls its cyclin D-cdk4 inhibitory activity. Mol. Cell Biol. 28, 498–510 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Blain, S. W., Montalvo, E. & Massague, J. Differential interaction of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 with cyclin A-Cdk2 and cyclin D2-Cdk4. J. Biol. Chem. 272, 25863–25872 (1997).

    Article  CAS  PubMed  Google Scholar 

  89. Russo, A. A., Tong, L., Lee, J. O., Jeffrey, P. D. & Pavletich, N. P. Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. Nature 395, 237–243 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Roussel, M. F. The INK4 family of cell cycle inhibitors in cancer. Oncogene 18, 5311–5317 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Takita, J. et al. Deletion map of chromosome 9 and p16 (CDKN2A) gene alterations in neuroblastoma. Cancer Res. 57, 907–912 (1997).

    CAS  PubMed  Google Scholar 

  92. Nobori, T. et al. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368, 753–756 (1994).

    Article  CAS  PubMed  Google Scholar 

  93. Boice, J. A. & Fairman, R. Structural characterization of the tumor suppressor p16, an ankyrin-like repeat protein. Protein Sci. 5, 1776–1784 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Coleman, K. G. et al. Identification of CDK4 sequences involved in cyclin D1 and p16 binding. J. Biol. Chem. 272, 18869–18874 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Ceha, H. M., Nasser, I., Medema, R. H. & Slebos, R. J. Several noncontiguous domains of CDK4 are involved in binding to the P16 tumor suppressor protein. Biochem. Biophys. Res. Commun. 249, 550–555 (1998).

    Article  CAS  PubMed  Google Scholar 

  96. Sotillo, R. et al. Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors. EMBO J. 20, 6637–6647 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Rane, S. G., Cosenza, S. C., Mettus, R. V. & Reddy, E. P. Germ line transmission of the Cdk4R24C mutation facilitates tumorigenesis and escape from cellular senescence. Mol. Cell Biol. 22, 644–656 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Foulkes, W. D., Flanders, T. Y., Pollock, P. M. & Hayward, N. K. The CDKN2A (p16) gene and human cancer. Mol. Med. 3, 5–20 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Jardim, D. L. et al. Cyclin pathway genomic alterations across 190,247 solid tumors: leveraging large-scale data to inform therapeutic directions. Oncologist 26, e78–e89 (2021).

    Article  CAS  PubMed  Google Scholar 

  100. Ueki, K. et al. CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res. 56, 150–153 (1996).

    CAS  PubMed  Google Scholar 

  101. Young, R. J. et al. Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines. Pigment. Cell Melanoma Res. 27, 590–600 (2014).

    Article  CAS  PubMed  Google Scholar 

  102. Maubec, E. et al. Characteristics of the coexistence of melanoma and renal cell carcinoma. Cancer 116, 5716–5724 (2010).

    Article  PubMed  Google Scholar 

  103. Ricketts, C. J. et al. The cancer genome atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 23, 313–326.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Latif, F. et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260, 1317–1320 (1993).

    Article  CAS  PubMed  Google Scholar 

  105. Nickerson, M. L. et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell 2, 157–164 (2002).

    Article  CAS  PubMed  Google Scholar 

  106. Zbar, B. et al. Hereditary papillary renal cell carcinoma: clinical studies in 10 families. J. Urol. 153, 907–912 (1995).

    Article  CAS  PubMed  Google Scholar 

  107. Grubb, R. L. 3rd et al. Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer. J. Urol. 177, 2074–2079; discussion 2079–2080 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Launonen, V. et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc. Natl Acad. Sci. USA 98, 3387–3392 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Jafri, M. et al. Germline mutations in the CDKN2B tumor suppressor gene predispose to renal cell carcinoma. Cancer Discov. 5, 723–729 (2015).

    Article  CAS  PubMed  Google Scholar 

  110. Zygmunt, A., Tedesco, V. C., Udho, E. & Krucher, N. A. Hypoxia stimulates p16 expression and association with cdk4. Exp. Cell Res. 278, 53–60 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Gump, J., Stokoe, D. & McCormick, F. Phosphorylation of p16INK4A correlates with Cdk4 association. J. Biol. Chem. 278, 6619–6622 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Jinno, S., Hung, S. C. & Okayama, H. Cell cycle start from quiescence controlled by tyrosine phosphorylation of Cdk4. Oncogene 18, 565–571 (1999).

    Article  CAS  PubMed  Google Scholar 

  113. Kato, J. Y., Matsuoka, M., Strom, D. K. & Sherr, C. J. Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase. Mol. Cell Biol. 14, 2713–2721 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Bisteau, X. et al. CDK4 T172 phosphorylation is central in a CDK7-dependent bidirectional CDK4/CDK2 interplay mediated by p21 phosphorylation at the restriction point. PLoS Genet. 9, e1003546 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Colleoni, B. et al. JNKs function as CDK4-activating kinases by phosphorylating CDK4 and p21. Oncogene 36, 4349–4361 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Blancquaert, S. et al. cAMP-dependent activation of mammalian target of rapamycin (mTOR) in thyroid cells. Implication in mitogenesis and activation of CDK4. Mol. Endocrinol. 24, 1453–1468 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Knudsen, E. S. et al. Cell cycle plasticity driven by MTOR signaling: integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer. Oncogene 38, 3355–3370 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Hartl, F. U., Bracher, A. & Hayer-Hartl, M. Molecular chaperones in protein folding and proteostasis. Nature 475, 324–332 (2011).

    Article  CAS  PubMed  Google Scholar 

  119. Walton-Diaz, A. et al. Contributions of co-chaperones and post-translational modifications towards Hsp90 drug sensitivity. Future Med. Chem. 5, 1059–1071 (2013).

    Article  CAS  PubMed  Google Scholar 

  120. Woodford, M. R. et al. Targeting Hsp90 in non-cancerous maladies. Curr. Top. Med. Chem. 16, 2792–2804 (2016).

    Article  CAS  PubMed  Google Scholar 

  121. Sima, S. & Richter, K. Regulation of the Hsp90 system. Biochim. Biophys. Acta Mol. Cell Res. 1865, 889–897 (2018).

    Article  CAS  PubMed  Google Scholar 

  122. Mayer, M. P. & Le Breton, L. Hsp90: breaking the symmetry. Mol. Cell 58, 8–20 (2015).

    Article  CAS  PubMed  Google Scholar 

  123. Rohl, A., Rohrberg, J. & Buchner, J. The chaperone Hsp90: changing partners for demanding clients. Trends Biochem. Sci. 38, 253–262 (2013).

    Article  PubMed  CAS  Google Scholar 

  124. Czemeres, J., Buse, K. & Verkhivker, G. M. Atomistic simulations and network-based modeling of the Hsp90-Cdc37 chaperone binding with Cdk4 client protein: a mechanism of chaperoning kinase clients by exploiting weak spots of intrinsically dynamic kinase domains. PLoS One 12, e0190267 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Verba, K. A. & Agard, D. A. How Hsp90 and Cdc37 lubricate kinase molecular switches. Trends Biochem. Sci. 42, 799–811 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lamphere, L. et al. Interaction between Cdc37 and Cdk4 in human cells. Oncogene 14, 1999–2004 (1997).

    Article  CAS  PubMed  Google Scholar 

  127. Zhao, Q., Boschelli, F., Caplan, A. J. & Arndt, K. T. Identification of a conserved sequence motif that promotes Cdc37 and cyclin D1 binding to Cdk4. J. Biol. Chem. 279, 12560–12564 (2004).

    Article  CAS  PubMed  Google Scholar 

  128. Truman, A. W. et al. CDK-dependent Hsp70 Phosphorylation controls G1 cyclin abundance and cell-cycle progression. Cell 151, 1308–1318 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Verba, K. A. et al. Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase. Science 352, 1542–1547 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Hallett, S. T. et al. Differential regulation of G1 CDK complexes by the Hsp90-Cdc37 chaperone system. Cell Rep. 21, 1386–1398 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Vaughan, C. K. et al. Structure of an Hsp90-Cdc37-Cdk4 complex. Mol. Cell 23, 697–707 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Vaughan, C. K. et al. Hsp90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc37. Mol. Cell 31, 886–895 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Mollapour, M. et al. Swe1Wee1-dependent tyrosine phosphorylation of Hsp90 regulates distinct facets of chaperone function. Mol. Cell 37, 333–343 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Backe, S. J., Sager, R. A., Woodford, M. R., Makedon, A. M. & Mollapour, M. Post-translational modifications of Hsp90 and translating the chaperone code. J. Biol. Chem. 295, 11099–11117 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Miyata, Y. & Nishida, E. CK2 binds, phosphorylates, and regulates its pivotal substrate Cdc37, an Hsp90-cochaperone. Mol. Cell Biochem. 274, 171–179 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. Oberoi, J. et al. Structural and functional basis of protein phosphatase 5 substrate specificity. Proc. Natl Acad. Sci. USA 113, 9009–9014 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Sager, R. A., Dushukyan, N., Woodford, M. & Mollapour, M. Structure and function of the co-chaperone protein phosphatase 5 in cancer. Cell Stress. Chaperones 25, 383–394 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Xu, W. et al. Dynamic tyrosine phosphorylation modulates cycling of the HSP90-P50(CDC37)-AHA1 chaperone machine. Mol. Cell 47, 434–443 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Bachman, A. B. et al. Phosphorylation induced cochaperone unfolding promotes kinase recruitment and client class-specific Hsp90 phosphorylation. Nat. Commun. 9, 265 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Smith, J. R. et al. Restricting direct interaction of CDC37 with HSP90 does not compromise chaperoning of client proteins. Oncogene 34, 15–26 (2015).

    Article  CAS  PubMed  Google Scholar 

  141. Lawless, N., Blacklock, K., Berrigan, E. & Verkhivker, G. Structural bioinformatics and protein docking analysis of the molecular chaperone-kinase interactions: towards allosteric inhibition of protein kinases by targeting the hsp90-cdc37 chaperone machinery. Pharmaceuticals 6, 1407–1428 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Zhu, J. et al. Cdc37 facilitates cell survival of colorectal carcinoma via activating the CDK4 signaling pathway. Cancer Sci. 109, 656–665 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Wang, Z., Wei, W., Sun, C. K., Chua, M. S. & So, S. Suppressing the CDC37 cochaperone in hepatocellular carcinoma cells inhibits cell cycle progression and cell growth. Liver Int. 35, 1403–1415 (2015).

    Article  PubMed  CAS  Google Scholar 

  144. D’Annessa, I. et al. Design of disruptors of the Hsp90-Cdc37 interface. Molecules 25, 360 (2020).

    Article  PubMed Central  CAS  Google Scholar 

  145. Paladino, A. et al. Chemical perturbation of oncogenic protein folding: from the prediction of locally unstable structures to the design of disruptors of hsp90-client interactions. Chemistry 26, 9459–9465 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Steinebach, C. et al. Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders. Chem. Sci. 11, 3474–3486 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Sherr, C. J., Beach, D. & Shapiro, G. I. Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov. 6, 353–367 (2016).

    Article  CAS  PubMed  Google Scholar 

  148. Soni, R. et al. Selective in vivo and in vitro effects of a small molecule inhibitor of cyclin-dependent kinase 4. J. Natl Cancer Inst. 93, 436–446 (2001).

    Article  CAS  PubMed  Google Scholar 

  149. Martin, M. P., Endicott, J. A. & Noble, M. E. M. Structure-based discovery of cyclin-dependent protein kinase inhibitors. Essays Biochem. 61, 439–452 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  150. De Azevedo, W. F. Jr et al. Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. Proc. Natl Acad. Sci. USA 93, 2735–2740 (1996).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Gray, N. S. et al. Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science 281, 533–538 (1998).

    Article  CAS  PubMed  Google Scholar 

  152. Ikuta, M. et al. Crystallographic approach to identification of cyclin-dependent kinase 4 (CDK4)-specific inhibitors by using CDK4 mimic CDK2 protein. J. Biol. Chem. 276, 27548–27554 (2001).

    Article  CAS  PubMed  Google Scholar 

  153. McInnes, C. et al. Structural determinants of CDK4 inhibition and design of selective ATP competitive inhibitors. Chem. Biol. 11, 525–534 (2004).

    Article  CAS  PubMed  Google Scholar 

  154. Park, H., Yeom, M. S. & Lee, S. Loop flexibility and solvent dynamics as determinants for the selective inhibition of cyclin-dependent kinase 4: comparative molecular dynamics simulation studies of CDK2 and CDK4. Chembiochem 5, 1662–1672 (2004).

    Article  CAS  PubMed  Google Scholar 

  155. Guan, H., Du, Y., Han, W., Shen, J. & Li, Q. Development of selective cyclin-dependent kinase 4 inhibitors for antineoplastic therapies. Anticancer. Agents Med. Chem. 17, 646–657 (2017).

    Article  CAS  PubMed  Google Scholar 

  156. Fry, D. W. et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol. Cancer Ther. 3, 1427–1438 (2004).

    CAS  PubMed  Google Scholar 

  157. Toogood, P. L. et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J. Med. Chem. 48, 2388–2406 (2005).

    Article  CAS  PubMed  Google Scholar 

  158. Cho, Y. S. et al. 4-(Pyrazol-4-yl)-pyrimidines as selective inhibitors of cyclin-dependent kinase 4/6. J. Med. Chem. 53, 7938–7957 (2010).

    Article  CAS  PubMed  Google Scholar 

  159. Gelbert, L. M. et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest. N. Drugs 32, 825–837 (2014).

    Article  CAS  Google Scholar 

  160. Wright, M. D. & Abraham, M. J. Preclinical discovery and development of abemaciclib used to treat breast cancer. Expert Opin. Drug Discov. 16, 485–496 (2021).

    Article  CAS  PubMed  Google Scholar 

  161. O’Brien, N. et al. Preclinical activity of abemaciclib alone or in combination with antimitotic and targeted therapies in breast cancer. Mol. Cancer Ther. 17, 897–907 (2018).

    Article  PubMed  CAS  Google Scholar 

  162. Torres-Guzman, R. et al. Preclinical characterization of abemaciclib in hormone receptor positive breast cancer. Oncotarget 8, 69493–69507 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Chen, P. et al. Spectrum and Degree of CDK drug interactions predicts clinical performance. Mol. Cancer Ther. 15, 2273–2281 (2016).

    Article  PubMed  CAS  Google Scholar 

  164. Knudsen, E. S., Hutcheson, J., Vail, P. & Witkiewicz, A. K. Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature. Oncotarget 8, 43678–43691 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Roberto, M. et al. CDK4/6 inhibitor treatments in patients with hormone receptor positive, Her2 negative advanced breast cancer: potential molecular mechanisms, clinical implications and future perspectives. Cancers 13, 332 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Singer, E. A., Golijanin, D. J., Miyamoto, H. & Messing, E. M. Androgen deprivation therapy for prostate cancer. Expert Opin. Pharmacother. 9, 211–228 (2008).

    Article  CAS  PubMed  Google Scholar 

  167. Finn, R. S. et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 11, R77 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Ertel, A. et al. RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response. Cell Cycle 9, 4153–4163 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Altucci, L. et al. 17beta-Estradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex activation and p105Rb phosphorylation during mitogenic stimulation of G1-arrested human breast cancer cells. Oncogene 12, 2315–2324 (1996).

    CAS  PubMed  Google Scholar 

  170. Dickler, M. N. et al. MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2− metastatic breast cancer. Clin. Cancer Res. 23, 5218–5224 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Li, J. et al. Cyclin-dependent kinase 4 and 6 inhibitors in hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer: a meta-analysis of randomized clinical trials. Breast Cancer Res. Treat. 180, 21–32 (2020).

    Article  CAS  PubMed  Google Scholar 

  172. Wang, L. et al. CDK4/6 inhibitors plus endocrine therapy improve overall survival in advanced HR+/HER2- breast cancer: a meta-analysis of randomized controlled trials. Breast J. 26, 1439–1443 (2019).

    Article  PubMed  Google Scholar 

  173. Deng, Y. et al. CDK4/6 inhibitors in combination with hormone therapy for HR+/HER2− advanced breast cancer: a systematic review and meta-analysis of randomized controlled trials. Clin. Breast Cancer 18, e943–e953 (2018).

    Article  CAS  PubMed  Google Scholar 

  174. Messina, C. et al. CDK4/6 inhibitors in advanced hormone receptor-positive/HER2-negative breast cancer: a systematic review and meta-analysis of randomized trials. Breast Cancer Res. Treat. 172, 9–21 (2018).

    Article  CAS  PubMed  Google Scholar 

  175. Gao, J. J. et al. CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis. Lancet Oncol. 21, 250–260 (2020).

    Article  CAS  PubMed  Google Scholar 

  176. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03701334 (2022).

  177. Johnston, S. R. D. et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2−, node-positive, high-risk, early breast cancer (monarchE). J. Clin. Oncol. 38, 3987–3998 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Curigliano, G. & Loibl, S. CDK4/6 inhibitors in breast cancer: one more step towards reduced mortality. Lancet Oncol. 21, 191–192 (2020).

    Article  PubMed  Google Scholar 

  179. Tan, A. R. et al. Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. 20, 1587–1601 (2019).

    Article  CAS  PubMed  Google Scholar 

  180. Al Baghdadi, T. et al. Sunitinib in patients with metastatic colorectal cancer (mCRC) with FLT-3 amplification: results from the targeted agent and profiling utilization registry (TAPUR) study. Target. Oncol. 15, 743–750 (2020).

    Article  PubMed  Google Scholar 

  181. Alva, A. S. et al. Pembrolizumab in patients with metastatic breast cancer with high tumor mutational burden: results from the targeted agent and profiling utilization registry (TAPUR) study. J. Clin. Oncol. 39, 2443–2451 (2021).

    Article  CAS  PubMed  Google Scholar 

  182. Fisher, J. G. et al. Cetuximab in patients with breast cancer, non-small cell lung cancer, and ovarian cancer without KRAS, NRAS, or BRAF mutations: results from the targeted agent and profiling utilization registry (TAPUR) study. Target. Oncol. 15, 733–741 (2020).

    Article  PubMed  Google Scholar 

  183. Flaherty, K. T. et al. Molecular landscape and actionable alterations in a genomically guided cancer clinical trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH). J. Clin. Oncol. 38, 3883–3894 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Tate, S. C. et al. A population pharmacokinetic and pharmacodynamic analysis of abemaciclib in a phase I clinical trial in cancer patients. Clin. Pharmacokinet. 57, 335–344 (2018).

    Article  CAS  PubMed  Google Scholar 

  185. Zhang, J. et al. A randomized phase I study of abemaciclib in Chinese patients with advanced and/or metastatic cancers. Target. Oncol. 16, 177–187 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Hussussian, C. J. et al. Germline p16 mutations in familial melanoma. Nat. Genet. 8, 15–21 (1994).

    Article  CAS  PubMed  Google Scholar 

  187. Kamb, A. et al. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat. Genet. 8, 23–26 (1994).

    Article  CAS  PubMed  Google Scholar 

  188. Zuo, L. et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat. Genet. 12, 97–99 (1996).

    Article  CAS  PubMed  Google Scholar 

  189. Teh, J. L. F. et al. Metabolic adaptations to MEK and CDK4/6 cotargeting in uveal melanoma. Mol. Cancer Ther. 19, 1719–1726 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Perez-Galan, P., Dreyling, M. & Wiestner, A. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood 117, 26–38 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Leonard, J. P. et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 119, 4597–4607 (2012).

    Article  CAS  PubMed  Google Scholar 

  192. Martin, P. et al. A phase I trial of palbociclib plus bortezomib in previously treated mantle cell lymphoma. Leuk. Lymphoma 60, 2917–2921 (2019).

    Article  CAS  PubMed  Google Scholar 

  193. Binh, M. B. et al. MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am. J. Surg. Pathol. 29, 1340–1347 (2005).

    Article  PubMed  Google Scholar 

  194. Dickson, M. A. et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J. Clin. Oncol. 31, 2024–2028 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Hadjadj, D. et al. A hypothesis-driven approach identifies CDK4 and CDK6 inhibitors as candidate drugs for treatments of adrenocortical carcinomas. Aging 9, 2695–2716 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Huang, S. et al. CDK4/6 inhibitor suppresses gastric cancer with CDKN2A mutation. Int. J. Clin. Exp. Med. 8, 11692–11700 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Frisone, D. et al. Durable response to palbociclib and letrozole in ovarian cancer with CDKN2A loss. Cancer Biol. Ther. 21, 197–202 (2020).

    Article  CAS  PubMed  Google Scholar 

  198. Rose, T. L. et al. Phase II trial of palbociclib in patients with metastatic urothelial cancer after failure of first-line chemotherapy. Br. J. Cancer 119, 801–807 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Gong, X. et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK6 inhibitor abemaciclib. Cancer Cell 32, 761–776.e6 (2017).

    Article  CAS  PubMed  Google Scholar 

  200. Green, J. L. et al. Direct CDKN2 modulation of CDK4 alters target engagement of CDK4 inhibitor drugs. Mol. Cancer Ther. 18, 771–779 (2019).

    Article  CAS  PubMed  Google Scholar 

  201. Iida, M. et al. The p21 levels have the potential to be a monitoring marker for ribociclib in breast cancer. Oncotarget 10, 4907–4918 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Vilgelm, A. E. et al. MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21. Sci. Transl. Med. 11, eaav7171 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. Pandey, K. et al. Combined CDK2 and CDK4/6 inhibition overcomes palbociclib resistance in breast cancer by enhancing senescence. Cancers 12, 3566 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  204. Bockstaele, L. et al. Regulated activating Thr172 phosphorylation of cyclin-dependent kinase 4(CDK4): its relationship with cyclins and CDK “inhibitors”. Mol. Cell Biol. 26, 5070–5085 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Raspe, E. et al. CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib. EMBO Mol. Med. 9, 1052–1066 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Pandey, K. et al. Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: a review. Int. J. Cancer 145, 1179–1188 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Pancholi, S. et al. Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities. Oncogene 39, 4781–4797 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Tong, Z. et al. Functional genomics identifies predictive markers and clinically actionable resistance mechanisms to CDK4/6 inhibition in bladder cancer. J. Exp. Clin. Cancer Res. 38, 322 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. Hua, H. et al. Targeting mTOR for cancer therapy. J. Hematol. Oncol. 12, 71 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Voss, M. H., Molina, A. M. & Motzer, R. J. mTOR inhibitors in advanced renal cell carcinoma. Hematol. Oncol. Clin. North. Am. 25, 835–852 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  211. Ghidini, M. et al. Clinical development of mTor inhibitors for renal cancer. Expert Opin. Investig. Drugs 26, 1229–1237 (2017).

    Article  CAS  PubMed  Google Scholar 

  212. Paternot, S. & Roger, P. P. Combined inhibition of MEK and mammalian target of rapamycin abolishes phosphorylation of cyclin-dependent kinase 4 in glioblastoma cell lines and prevents their proliferation. Cancer Res. 69, 4577–4581 (2009).

    Article  CAS  PubMed  Google Scholar 

  213. Zacharek, S. J., Xiong, Y. & Shumway, S. D. Negative regulation of TSC1–TSC2 by mammalian D-type cyclins. Cancer Res. 65, 11354–11360 (2005).

    Article  CAS  PubMed  Google Scholar 

  214. Kim, J. & Guan, K. L. mTOR as a central hub of nutrient signalling and cell growth. Nat. Cell Biol. 21, 63–71 (2019).

    Article  CAS  PubMed  Google Scholar 

  215. Pikman, Y. et al. Synergistic drug combinations with a CDK4/6 inhibitor in T-cell acute lymphoblastic leukemia. Clin. Cancer Res. 23, 1012–1024 (2017).

    Article  CAS  PubMed  Google Scholar 

  216. Modiano, J. F., Domenico, J., Szepesi, A., Lucas, J. J. & Gelfand, E. W. Differential requirements for interleukin-2 distinguish the expression and activity of the cyclin-dependent kinases Cdk4 and Cdk2 in human T cells. J. Biol. Chem. 269, 32972–32978 (1994).

    Article  CAS  PubMed  Google Scholar 

  217. Modiano, J. F., Mayor, J., Ball, C., Fuentes, M. K. & Linthicum, D. S. CDK4 expression and activity are required for cytokine responsiveness in T cells. J. Immunol. 165, 6693–6702 (2000).

    Article  CAS  PubMed  Google Scholar 

  218. Macian, F. NFAT proteins: key regulators of T-cell development and function. Nat. Rev. Immunol. 5, 472–484 (2005).

    Article  CAS  PubMed  Google Scholar 

  219. Jin, X. et al. Phosphorylated RB promotes cancer immunity by inhibiting NF-kappaB activation and PD-L1 expression. Mol. Cell 73, 22–35 e26 (2019).

    Article  CAS  PubMed  Google Scholar 

  220. Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl Acad. Sci. USA 99, 12293–12297 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Sato, H., Okonogi, N. & Nakano, T. Rationale of combination of anti-PD-1/PD-L1 antibody therapy and radiotherapy for cancer treatment. Int. J. Clin. Oncol. 25, 801–809 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03905889 (2022).

  224. O’Brien, J., Hayder, H., Zayed, Y. & Peng, C. Overview of MicroRNA biogenesis, mechanisms of actions, and circulation. Front. Endocrinol. 9, 402 (2018).

    Article  Google Scholar 

  225. Xiao, H. et al. MiR-1 downregulation correlates with poor survival in clear cell renal cell carcinoma where it interferes with cell cycle regulation and metastasis. Oncotarget 6, 13201–13215 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Xiao, H. et al. miR-206 functions as a novel cell cycle regulator and tumor suppressor in clear-cell renal cell carcinoma. Cancer Lett. 374, 107–116 (2016).

    Article  CAS  PubMed  Google Scholar 

  227. Statello, L., Guo, C. J., Chen, L. L. & Huarte, M. Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell Biol. 22, 96–118 (2021).

    Article  CAS  PubMed  Google Scholar 

  228. Chen, D., Sun, X., Zhang, X. & Cao, J. Inhibition of the CDK4/6-Cyclin D-Rb pathway by ribociclib augments chemotherapy and immunotherapy in renal cell carcinoma. Biomed. Res. Int. 2020, 9525207 (2020).

    PubMed  PubMed Central  Google Scholar 

  229. Clark, D. J. et al. Integrated proteogenomic characterization of clear cell renal cell carcinoma. Cell 179, 964–983.e31 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Logan, J. E. et al. PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity. Anticancer. Res. 33, 2997–3004 (2013).

    CAS  PubMed  Google Scholar 

  231. Semenza, G. L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3, 721–732 (2003).

    Article  CAS  PubMed  Google Scholar 

  232. Jonasch, E. et al. Belzutifan for renal cell carcinoma in Von Hippel-Lindau disease. N. Engl. J. Med. 385, 2036–2046 (2021).

    Article  CAS  PubMed  Google Scholar 

  233. Atkins, D. J. et al. Concomitant deregulation of HIF1alpha and cell cycle proteins in VHL-mutated renal cell carcinomas. Virchows Arch. 447, 634–642 (2005).

    Article  PubMed  Google Scholar 

  234. Schodel, J. et al. Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1 expression. Nat. Genet. 44, 420–425 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  235. Bailey, S. T. et al. MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma. Nat. Commun. 8, 15770 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Bommi-Reddy, A. et al. Kinase requirements in human cells. III. Altered kinase requirements in VHL−/− cancer cells detected in a pilot synthetic lethal screen. Proc. Natl Acad. Sci. USA 105, 16484–16489 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Zhu, G. et al. Synthesis, structure-activity relationship, and biological studies of indolocarbazoles as potent cyclin D1-CDK4 inhibitors. J. Med. Chem. 46, 2027–2030 (2003).

    Article  CAS  PubMed  Google Scholar 

  238. Nicholson, H. E. et al. HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species. Sci. Signal 12, eaay0482 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Small, J., Washburn, E., Millington, K., Zhu, J. & Holder, S. L. The addition of abemaciclib to sunitinib induces regression of renal cell carcinoma xenograft tumors. Oncotarget 8, 95116–95134 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  240. Anand, P., Sundaram, C., Jhurani, S., Kunnumakkara, A. B. & Aggarwal, B. B. Curcumin and cancer: an “old-age” disease with an “age-old” solution. Cancer Lett. 267, 133–164 (2008).

    Article  CAS  PubMed  Google Scholar 

  241. Mukhopadhyay, A. et al. Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation. Oncogene 21, 8852–8861 (2002).

    Article  CAS  PubMed  Google Scholar 

  242. Debata, P. R. et al. Curcumin potentiates the ability of sunitinib to eliminate the VHL-lacking renal cancer cells 786-O: rapid inhibition of Rb phosphorylation as a preamble to cyclin D1 inhibition. Anticancer. Agents Med. Chem. 13, 1508–1513 (2013).

    Article  CAS  PubMed  Google Scholar 

  243. Wang, Y. et al. Wogonin induces apoptosis and reverses sunitinib resistance of renal cell carcinoma cells via inhibiting CDK4-RB pathway. Front. Pharmacol. 11, 1152 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04594005 (2021).

  245. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02065063 (2018).

  246. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02022982 (2022).

  247. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03310879 (2022).

  248. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02693535 (2022).

  249. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02465060 (2022).

  250. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03297606 (2021).

  251. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03239015 (2020).

  252. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03065062 (2022).

  253. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT01522989 (2020).

  254. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03237390 (2021).

  255. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04116541 (2021).

  256. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04557449 (2022).

  257. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02919696 (2020).

  258. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT01394016 (2021).

  259. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03965845 (2021).

  260. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04439201 (2022).

  261. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02389842 (2019).

  262. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04162301 (2021).

  263. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04060511 (2019).

  264. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04275050 (2020).

  265. Cho, Y. S. et al. Fragment-based discovery of 7-azabenzimidazoles as potent, highly selective, and orally active CDK4/6 inhibitors. ACS Med. Chem. Lett. 3, 445–449 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are grateful to W. Marston Linehan (Urologic Oncology Branch, NCI) for his scientific contribution. This work was partly supported by the National Institute of General Medical Sciences with the NIH (grants R35GM139584, R01GM124256 and DoD KC190038 (M.M.), and R01GM139932 (D.B.)). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was also supported by funds from SUNY Upstate Medical University and the Upstate Foundation (D.B. and M.M.).

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  1. Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA

    Rebecca A. Sager, Sarah J. Backe, Elham Ahanin, Garrett Smith, Imad Nsouli, Mark R. Woodford, Gennady Bratslavsky, Dimitra Bourboulia & Mehdi Mollapour

  2. Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA

    Rebecca A. Sager, Sarah J. Backe, Elham Ahanin, Garrett Smith, Imad Nsouli, Mark R. Woodford, Gennady Bratslavsky, Dimitra Bourboulia & Mehdi Mollapour

  3. Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA

    Sarah J. Backe, Elham Ahanin, Mark R. Woodford, Gennady Bratslavsky, Dimitra Bourboulia & Mehdi Mollapour

  4. Syracuse VA Medical Center, Syracuse, NY, USA

    Imad Nsouli & Mehdi Mollapour

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Contributions

M.M., R.A.S., G.E.S. and I.N. researched data for article. M.M., R.A.S., S.J.B., G.B. and D.B. made substantial contribution to the discussion of content. M.M., R.A.S., S.J.B., E.A. and M.R.W. wrote the article. M.M., R.A.S. and S.J.B. reviewed/edited the manuscript before submission

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Correspondence to Mehdi Mollapour.

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Sager, R.A., Backe, S.J., Ahanin, E. et al. Therapeutic potential of CDK4/6 inhibitors in renal cell carcinoma. Nat Rev Urol 19, 305–320 (2022). https://doi.org/10.1038/s41585-022-00571-8

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