Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

At a crossroads: how to translate the roles of PI3K in oncogenic and metabolic signalling into improvements in cancer therapy

Abstract

Numerous agents targeting various phosphatidylinositol 3-kinase (PI3K) pathway components, including PI3K, AKT and mTOR, have been tested in oncology clinical trials, resulting in regulatory approvals for the treatment of selected patients with breast cancer, certain other solid tumours or particular haematological malignancies. However, given the prominence of PI3K signalling in cancer and the crucial role of this pathway in linking cancer growth with metabolism, these clinical results could arguably be improved upon. In this Review, we discuss past and present efforts to overcome the somewhat limited clinical efficacy of PI3Kα pathway inhibitors, including optimization of inhibitor specificity, patient selection and biomarkers across cancer types, with a focus on breast cancer, as well as identification and abrogation of signalling-related and metabolic mechanisms of resistance, and interventions to improve management of prohibitive adverse events. We highlight the advantages and limitations of laboratory-based model systems used to study the PI3K pathway, and propose technologies and experimental inquiries to guide the future clinical deployment of PI3K pathway inhibitors in the treatment of cancer.

Key points

  • PIK3CA is one of the most frequently mutated genes in cancer; the PI3K pathway is altered in a large number of cancer types, driving cell signalling, growth and metabolism, and PI3K inhibitors have been in development for over four decades.

  • Seven drugs that target the PI3K pathway have received regular or accelerated approval from the FDA, including alpelisib in combination with fulvestrant for advanced-stage, PIK3CA-mutant, oestrogen receptor-positive breast cancer. AKT inhibitors and next-generation mTOR inhibitors are currently being tested in early phase and late-phase clinical trials.

  • Adaptive signalling, epigenetic and metabolic changes in cancer cells can limit the clinical efficacy of PI3K inhibitors. In addition, PI3K inhibition in non-cancer cells causes hyperglycaemia and other on-target adverse effects that limit patient tolerability, as well as hyperinsulinaemia, which can lead to reactivation of cancer cells; the net effect of these alterations is attenuation of PI3K inhibitor efficacy.

  • Targeting insulin signalling, improved management of hyperglycaemia, development of mutant-specific PI3K inhibitors, and validation of refined biomarkers of response and resistance are novel translational strategies currently being tested to improve the therapeutic window of PI3K inhibitors in patients with cancer.

  • Genomic, transcriptomic, proteomic, phosphoproteomic and metabolomic analyses of patients with PIK3CA-mutant tumours receiving PI3K inhibitors are needed to discover new pathways for combination therapies in different cancer types.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: The PI3K pathway in non-malignant cells and cancer.
Fig. 2: Drugging the PI3K pathway through the decades.
Fig. 3: Signalling and epigenetic mechanisms limiting the efficacy of PI3K inhibitors.
Fig. 4: Metabolic mechanisms limiting the efficacy of PI3K inhibitors.

References

  1. Fruman, D. A. et al. The PI3K pathway in human disease. Cell 170, 605–635 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Vanhaesebroeck, B., Perry, M. W. D., Brown, J. R., Andre, F. & Okkenhaug, K. PI3K inhibitors are finally coming of age. Nat. Rev. Drug Discov. 20, 741–769 (2021).

    Article  CAS  PubMed  Google Scholar 

  3. Castel, P., Toska, E., Engelman, J. A. & Scaltriti, M. The present and future of PI3K inhibitors for cancer therapy. Nat. Cancer 2, 587–597 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hanker, A. B., Kaklamani, V. & Arteaga, C. L. Challenges for the clinical development of PI3K inhibitors: strategies to improve their impact in solid tumors. Cancer Discov. 9, 482–491 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Whitman, M., Kaplan, D. R., Schaffhausen, B., Cantley, L. & Roberts, T. M. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 315, 239–242 (1985).

    Article  CAS  PubMed  Google Scholar 

  6. Whitman, M., Downes, C. P., Keeler, M., Keller, T. & Cantley, L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature 332, 644–646 (1988).

    Article  CAS  PubMed  Google Scholar 

  7. Auger, K. R., Serunian, L. A., Soltoff, S. P., Libby, P. & Cantley, L. C. PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell 57, 167–175 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. Ruderman, N. B., Kapeller, R., White, M. F. & Cantley, L. C. Activation of phosphatidylinositol 3-kinase by insulin. Proc. Natl Acad. Sci. USA 87, 1411–1415 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Manning, B. D. & Toker, A. AKT/PKB signaling: navigating the network. Cell 169, 381–405 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Samuels, Y. et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7, 561–573 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Huang, C. H. et al. The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318, 1744–1748 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Miller, M. S. et al. Structural basis of nSH2 regulation and lipid binding in PI3Kα. Oncotarget 5, 5198–5208 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Mandelker, D. et al. A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane. Proc. Natl Acad. Sci. USA 106, 16996–17001 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Thorpe, L. M. et al. PI3K-p110alpha mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K-p85alpha. Proc. Natl Acad. Sci. USA 114, 7095–7100 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chagpar, R. B. et al. Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase. Proc. Natl Acad. Sci. USA 107, 5471–5476 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cheung, L. W. et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 1, 170–185 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cheung, L. W. et al. Regulation of the PI3K pathway through a p85alpha monomer-homodimer equilibrium. eLife 4, e06866 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cheung, L. W. et al. Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors. Cancer Cell 26, 479–494 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 174, 1034–1035 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nussinov, R., Tsai, C. J. & Jang, H. Ras assemblies and signaling at the membrane. Curr. Opin. Struct. Biol. 62, 140–148 (2020).

    Article  CAS  PubMed  Google Scholar 

  22. Pacold, M. E. et al. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma. Cell 103, 931–943 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Hornbeck, P. V. et al. 15 Years of PhosphoSitePlus(R): integrating post-translationally modified sites, disease variants and isoforms. Nucleic Acids Res. 47, D433–D441 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Klarenbeek, S., van Miltenburg, M. H. & Jonkers, J. Genetically engineered mouse models of PI3K signaling in breast cancer. Mol. Oncol. 7, 146–164 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wu, X. et al. Activation of diverse signalling pathways by oncogenic PIK3CA mutations. Nat. Commun. 5, 4961 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Moniz, L. S. et al. Phosphoproteomic comparison of Pik3ca and Pten signalling identifies the nucleotidase NT5C as a novel AKT substrate. Sci. Rep. 7, 39985 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Madsen, R. R. et al. Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner. Proc. Natl Acad. Sci. USA 116, 8380–8389 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Parsons, R. Discovery of the PTEN tumor suppressor and its connection to the PI3K and AKT oncogenes. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a036129 (2020).

    Article  PubMed  Google Scholar 

  29. Lee, Y. R., Chen, M. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat. Rev. Mol. Cell Biol. 19, 547–562 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Wymann, M. P. et al. Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol. Cell Biol. 16, 1722–1733 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Walker, E. H. et al. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol. Cell 6, 909–919 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Vlahos, C. J., Matter, W. F., Hui, K. Y. & Brown, R. F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J. Biol. Chem. 269, 5241–5248 (1994).

    Article  CAS  PubMed  Google Scholar 

  33. Bendell, J. C. et al. A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors. Invest. New Drugs 33, 463–471 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Rodon, J. et al. Phase 1/1b dose escalation and expansion study of BEZ235, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumors including patients with advanced breast cancer. Cancer Chemother. Pharmacol. 82, 285–298 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Carlo, M. I. et al. A phase Ib study of BEZ235, a dual inhibitor of phosphatidylinositol 3-kinase (pi3k) and mammalian target of rapamycin (mTOR), in patients with advanced renal cell carcinoma. Oncologist 21, 787–788 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lukey, P. T. et al. A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis. Eur. Respir. J. https://doi.org/10.1183/13993003.01992-2018 (2019).

    Article  PubMed  Google Scholar 

  37. Hettiarachchi, S. U. et al. Targeted inhibition of PI3 kinase/mTOR specifically in fibrotic lung fibroblasts suppresses pulmonary fibrosis in experimental models. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aay3724 (2020).

    Article  PubMed  Google Scholar 

  38. Rodon, J. et al. Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Invest. New Drugs 32, 670–681 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Miller, T. W. et al. ERalpha-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov. 1, 338–351 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bosch, A. et al. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci. Transl. Med. 7, 283ra251 (2015).

    Article  CAS  Google Scholar 

  41. Ma, C. X. et al. A phase I trial of BKM120 (Buparlisib) in combination with fulvestrant in postmenopausal women with estrogen receptor-positive metastatic breast cancer. Clin. Cancer Res. 22, 1583–1591 (2016).

    Article  CAS  PubMed  Google Scholar 

  42. Baselga, J. et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 18, 904–916 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Di Leo, A. et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 19, 87–100 (2018).

    Article  PubMed  Google Scholar 

  44. Dent, S. et al. Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial. Ann. Oncol. 32, 197–207 (2021).

    Article  CAS  PubMed  Google Scholar 

  45. Andre, F. et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N. Engl. J. Med. 380, 1929–1940 (2019).

    Article  CAS  PubMed  Google Scholar 

  46. Narayan, P. et al. FDA approval summary: alpelisib plus fulvestrant for patients with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer. Clin. Cancer Res. 27, 1842–1849 (2021).

    Article  CAS  PubMed  Google Scholar 

  47. Andre, F. et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann. Oncol. 32, 208–217 (2021).

    Article  CAS  PubMed  Google Scholar 

  48. Jhaveri, K. et al. Phase I basket study of taselisib, an isoform-selective PI3K inhibitor, in patients with PIK3CA-mutant cancers. Clin. Cancer Res. 27, 447–459 (2021).

    Article  CAS  PubMed  Google Scholar 

  49. Juric, D. et al. Phosphatidylinositol 3-kinase alpha-selective inhibition with alpelisib (BYL719) in PIK3CA-altered solid tumors: results from the first-in-human study. J. Clin. Oncol. 36, 1291–1299 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ciruelos, E. M. et al. Patient-reported outcomes in patients with PIK3CA-mutated hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer from SOLAR-1. J. Clin. Oncol. 39, 2005–2015 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rugo, H. S. et al. Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer. Ann. Oncol. 31, 1001–1010 (2020).

    Article  CAS  PubMed  Google Scholar 

  52. Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Janku, F., Yap, T. A. & Meric-Bernstam, F. Targeting the PI3K pathway in cancer: are we making headway? Nat. Rev. Clin. Oncol. 15, 273–291 (2018).

    Article  CAS  PubMed  Google Scholar 

  54. Iyer, G. et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 338, 221 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wagle, N. et al. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N. Engl. J. Med. 371, 1426–1433 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Rugo, H. S. et al. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial. Lancet Oncol. 18, 654–662 (2017).

    Article  CAS  PubMed  Google Scholar 

  57. Hudes, G. et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2281 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Motzer, R. J. et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116, 4256–4265 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Piccart, M. et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2dagger. Ann. Oncol. 25, 2357–2362 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yao, J. C. et al. Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: overall survival and circulating biomarkers from the randomized, phase III RADIANT-3 study. J. Clin. Oncol. 34, 3906–3913 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Biondo, A. et al. Phase I clinical trial of an allosteric AKT inhibitor, MK-2206, using a once weekly (QW) dose regimen in patients with advanced solid tumors. J. Clin. Oncol. 29, 3037–3037 (2011).

    Article  Google Scholar 

  62. Hyman, D. et al. Abstract CT035: a phase Ib study of miransertib (ARQ 092) in combination with anastrozole in patients with PIK3CA or AKT1-mutant ER+ endometrial or ovarian cancer. Cancer Res. 78, CT035–CT035 (2018).

    Google Scholar 

  63. Schneeweiss, A. et al. Phase 1 dose escalation study of the allosteric AKT Inhibitor BAY 1125976 in advanced solid cancer-lack of association between activating AKT mutation and AKT inhibition-derived efficacy. Cancers https://doi.org/10.3390/cancers11121987 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Yunokawa, M. et al. First-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumours. Ann. Oncol. 30, v169 (2019).

    Article  Google Scholar 

  65. Banerji, U. et al. A Phase I open-label study to identify a dosing regimen of the Pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA-mutated breast and gynecologic cancers. Clin. Cancer Res. 24, 2050–2059 (2018).

    Article  CAS  PubMed  Google Scholar 

  66. Saura, C. et al. A first-in-human phase I study of the ATP-competitive AKT inhibitor ipatasertib demonstrates robust and safe targeting of AKT in patients with solid tumors. Cancer Discov. 7, 102–113 (2017).

    Article  CAS  PubMed  Google Scholar 

  67. Turner, N. C. et al. BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population. Ann. Oncol. 30, 774–780 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Jones, R. H. et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 21, 345–357 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Smyth, L. M. et al. Capivasertib, an AKT kinase inhibitor, as monotherapy or in combination with fulvestrant in patients with AKT1 (E17K)-mutant, ER-positive metastatic breast cancer. Clin. Cancer Res. 26, 3947–3957 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kalinsky, K. et al. Effect of capivasertib in patients with an AKT1 E17K-mutated tumor: NCI-MATCH subprotocol EAY131-Y nonrandomized trial. JAMA Oncol. 7, 271–278 (2021).

    Article  PubMed  Google Scholar 

  71. Turner, N. et al. 350TiP A phase III trial of capivasertib and fulvestrant versus placebo and fulvestrant in patients with HR+/HER2 breast cancer (CAPItello-291). Ann. Oncol. 31 (Suppl. 4), S388–S389 (2020).

    Article  Google Scholar 

  72. Hamilton, E. et al. 338TiP CAPItello-292: a phase 1b/3 study of capivasertib, palbociclib and fulvestrant versus placebo, palbociclib and fulvestrant in HR+/HER2 advanced breast cancer. Ann. Oncol. 32, S514 (2021).

    Article  Google Scholar 

  73. Schmid, P. et al. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J. Clin. Oncol. 38, 423–433 (2020).

    Article  CAS  PubMed  Google Scholar 

  74. Schmid, P. et al. Abstract OT2-08-02: Capivasertib and paclitaxel in first-line treatment of patients with metastatic triple-negative breast cancer: a phase III trial (CAPItello-290). Cancer Res. https://doi.org/10.1158/1538-7445.SABCS19-OT2-08-02 (2020).

    Article  PubMed  Google Scholar 

  75. Kim, S. B. et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 18, 1360–1372 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Dent, R. et al. Double-blind placebo-controlled randomized phase III trial evaluating first-line ipatasertib combined with paclitaxel for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer: primary results from IPATunity130 Cohort A. 2020 San Antonio Breast Cancer Symposium. Abstract GS3-04. Cancer Res. https://doi.org/10.1158/1538-7445.SABCS20-GS3-04 (2021).

    Article  Google Scholar 

  77. de Bono, J. S. et al. Randomized phase II study evaluating akt blockade with ipatasertib, in combination with abiraterone, in patients with metastatic prostate cancer with and without PTEN loss. Clin. Cancer Res. 25, 928–936 (2019).

    Article  PubMed  Google Scholar 

  78. Sweeney, C. et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Lancet 398, 131–142 (2021).

    Article  CAS  PubMed  Google Scholar 

  79. Juric, D. et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kalpha inhibitor. Nature 518, 240–244 (2015).

    Article  CAS  PubMed  Google Scholar 

  80. Razavi, P. et al. Alterations in PTEN and ESR1 promote clinical resistance to alpelisib plus aromatase inhibitors. Nat. Cancer 1, 382–393 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Maheshwari, S. et al. Kinetic and structural analyses reveal residues in phosphoinositide 3-kinase alpha that are critical for catalysis and substrate recognition. J. Biol. Chem. 292, 13541–13550 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Elkabets, M. et al. mTORC1 inhibition is required for sensitivity to PI3K p110alpha inhibitors in PIK3CA-mutant breast cancer. Sci. Transl. Med. 5, 196ra199 (2013).

    Article  CAS  Google Scholar 

  84. Castel, P. et al. PDK1-SGK1 signaling sustains AKT-independent mTORC1 activation and confers resistance to PI3Kalpha inhibition. Cancer Cell 30, 229–242 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Gasser, J. A. et al. SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer. Mol. Cell 56, 595–607 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Le, X. et al. Systematic functional characterization of resistance to PI3K inhibition in breast cancer. Cancer Discov. 6, 1134–1147 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Cai, Y. et al. Genomic alterations in PIK3CA-mutated breast cancer result in mTORC1 activation and limit the sensitivity to PI3Kalpha inhibitors. Cancer Res. 81, 2470–2480 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Chandarlapaty, S. et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19, 58–71 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Zorea, J. et al. IGF1R upregulation confers resistance to isoform-specific inhibitors of PI3K in PIK3CA-driven ovarian cancer. Cell Death Dis. 9, 944 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Schwartz, S. et al. Feedback suppression of PI3Kalpha signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kbeta. Cancer Cell 27, 109–122 (2015).

    Article  CAS  PubMed  Google Scholar 

  91. Elkabets, M. et al. AXL mediates resistance to PI3Kalpha inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas. Cancer Cell 27, 533–546 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Drago, J. Z. et al. FGFR1 amplification mediates endocrine resistance but retains TORC sensitivity in metastatic hormone receptor-positive (HR+) breast cancer. Clin. Cancer Res. 25, 6443–6451 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Curigliano, G. et al. Alpelisib in combination with everolimus +/- exemestane in solid tumours: phase Ib randomised, open-label, multicentre study. Eur. J. Cancer 151, 49–62 (2021).

    Article  CAS  PubMed  Google Scholar 

  94. Juric, D. et al. 342A Phase Ib/II study of alpelisib (BYL719) and ganitumab (AMG 479) in adult patients with selected advanced solid tumors. Eur. J. Cancer 51, S68 (2015).

    Article  Google Scholar 

  95. Hyman, D. M. et al. Combined PIK3CA and FGFR inhibition with alpelisib and infigratinib in patients with PIK3CA-mutant solid tumors, with or without FGFR alterations. JCO Precis. Oncl. https://doi.org/10.1200/po.19.00221 (2019).

    Article  Google Scholar 

  96. Toska, E. et al. PI3K inhibition activates SGK1 via a feedback loop to promote chromatin-based regulation of ER-dependent gene expression. Cell Rep. 27, 294–306.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Toska, E. et al. PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D. Science 355, 1324–1330 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hopkins, B. D. et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560, 499–503 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hopkins, B. D., Goncalves, M. D. & Cantley, L. C. Obesity and cancer mechanisms: cancer metabolism. J. Clin. Oncol. 34, 4277–4283 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Newman, J. C. & Verdin, E. Ketone bodies as signaling metabolites. Trends Endocrinol. Metab. 25, 42–52 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. Shimazu, T. et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Jiang, Z. et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 20, 806–815 (2019).

    Article  CAS  PubMed  Google Scholar 

  103. U.S. National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT05090358 (2021).

  104. Caffa, I. et al. Fasting-mimicking diet and hormone therapy induce breast cancer regression. Nature 583, 620–624 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Vernieri, C. et al. Fasting-mimicking diet is safe and reshapes metabolism and antitumor immunity in cancer patients. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-21-0030 (2021).

    Article  PubMed  Google Scholar 

  106. Vasan, N. et al. Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kalpha inhibitors. Science 366, 714–723 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Hong, R. et al. Abstract PD4-14: GDC-0077 is a selective PI3Kalpha inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies. Cancer Res. 78 (Suppl. 4), PD4-14 (2018).

    Google Scholar 

  108. Bedard, P. L. et al. Abstract PD1-02: A phase I/Ib study evaluating GDC-0077 + palbociclib (palbo) + fulvestrant in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC). Cancer Res. 81 (Suppl. 4), PD1-02 (2021).

    Google Scholar 

  109. U.S. National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03006172 (2016).

  110. Song, K. W. et al. RTK-dependent inducible degradation of mutant PI3Kalpha drives GDC-0077 (Inavolisib) efficacy. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-21-0072 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Hon, W. C., Berndt, A. & Williams, R. L. Regulation of lipid binding underlies the activation mechanism of class IA PI3-kinases. Oncogene 31, 3655–3666 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. Pazolli, E. et al. Discovery and characterization of RLY2608, the first allosteric, mutant, and isoform-selective inhibitor of PI3Kα. In AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics (AACR, NCI, EORTC, 2021).

  113. Klippel, A. et al. Preclinical characterization of LOXO-783 (LOX-22783), a highly potent, mutantselective and brain-penetrant allosteric PI3Kα H1047R inhibitor. In AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics (AACR, NCI, EORTC, 2021).

  114. Liu, X. et al. Cryo-EM structures of PI3Kalpha reveal conformational changes during inhibition and activation. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2109327118 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Burke, J. E., Perisic, O., Masson, G. R., Vadas, O. & Williams, R. L. Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110alpha (PIK3CA). Proc. Natl Acad. Sci. USA 109, 15259–15264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Dang, C. V., Le, A. & Gao, P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin. Cancer Res. 15, 6479–6483 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Venkatesh, H. S. et al. Reduced phosphocholine and hyperpolarized lactate provide magnetic resonance biomarkers of PI3K/Akt/mTOR inhibition in glioblastoma. Neuro-Oncology 14, 315–325 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Ward, C. S. et al. Noninvasive detection of target modulation following phosphatidylinositol 3-kinase inhibition using hyperpolarized 13C magnetic resonance spectroscopy. Cancer Res. 70, 1296–1305 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ros, S. et al. Metabolic imaging detects resistance to PI3Kalpha inhibition mediated by persistent FOXM1 expression in ER+ breast cancer. Cancer Cell 38, 516–533.e9 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Koundouros, N. et al. Metabolic fingerprinting links oncogenic PIK3CA with enhanced arachidonic acid-derived eicosanoids. Cell 181, 1596–1611.e27 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Hoxhaj, G. & Manning, B. D. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat. Rev. Cancer 20, 74–88 (2020).

    Article  CAS  PubMed  Google Scholar 

  122. Gottlob, K. et al. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 15, 1406–1418 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Deprez, J., Vertommen, D., Alessi, D. R., Hue, L. & Rider, M. H. Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J. Biol. Chem. 272, 17269–17275 (1997).

    Article  CAS  PubMed  Google Scholar 

  124. Saha, A. et al. Akt phosphorylation and regulation of transketolase is a nodal point for amino acid control of purine synthesis. Mol. Cell 55, 264–276 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Hoxhaj, G. et al. Direct stimulation of NADP+ synthesis through Akt-mediated phosphorylation of NAD kinase. Science 363, 1088–1092 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Potapova, I. A., El-Maghrabi, M. R., Doronin, S. V. & Benjamin, W. B. Phosphorylation of recombinant human ATP:citrate lyase by cAMP-dependent protein kinase abolishes homotropic allosteric regulation of the enzyme by citrate and increases the enzyme activity. Allosteric activation of ATP:citrate lyase by phosphorylated sugars. Biochemistry 39, 1169–1179 (2000).

    Article  CAS  PubMed  Google Scholar 

  127. Kovacina, K. S. et al. Identification of a proline-rich Akt substrate as a 14-3-3 binding partner. J. Biol. Chem. 278, 10189–10194 (2003).

    Article  CAS  PubMed  Google Scholar 

  128. Waldhart, A. N. et al. Phosphorylation of TXNIP by AKT mediates acute influx of glucose in response to insulin. Cell Rep. 19, 2005–2013 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J. & Cantley, L. C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 10, 151–162 (2002).

    Article  CAS  PubMed  Google Scholar 

  130. Hu, H. et al. Phosphoinositide 3-kinase regulates glycolysis through mobilization of aldolase from the actin cytoskeleton. Cell 164, 433–446 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. You, I. et al. Discovery of an AKT degrader with prolonged inhibition of downstream signaling. Cell Chem. Biol. 27, 66–73.e7 (2020).

    Article  CAS  PubMed  Google Scholar 

  132. Xu, J. et al. AKT degradation selectively inhibits the growth of PI3K/PTEN pathway-mutant cancers with wild-type KRAS and BRAF by destabilizing aurora kinase B. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-20-0815 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Lee, B. J. et al. Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth. Nat. Chem. Biol. 17, 1065–1074 (2021).

    Article  CAS  PubMed  Google Scholar 

  134. Tate, J. G. et al. COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res. 47, D941–D947 (2019).

    Article  CAS  PubMed  Google Scholar 

  135. Gustin, J. P. et al. Knockin of mutant PIK3CA activates multiple oncogenic pathways. Proc. Natl Acad. Sci. USA 106, 2835–2840 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Dogruluk, T. et al. Identification of variant-specific functions of PIK3CA by rapid phenotyping of rare mutations. Cancer Res. 75, 5341–5354 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Croessmann, S. et al. PIK3CA C2 domain deletions hyperactivate phosphoinositide 3-kinase (PI3K), generate oncogene dependence, and are exquisitely sensitive to PI3Kalpha Inhibitors. Clin. Cancer Res. 24, 1426–1435 (2018).

    Article  CAS  PubMed  Google Scholar 

  138. Spangle, J. M. et al. PIK3CA C-terminal frameshift mutations are novel oncogenic events that sensitize tumors to PI3K-alpha inhibition. Proc. Natl Acad. Sci. USA 117, 24427–24433 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Saito, Y. et al. Landscape and function of multiple mutations within individual oncogenes. Nature 582, 95–99 (2020).

    Article  CAS  PubMed  Google Scholar 

  140. Madsen, R. R. & Vanhaesebroeck, B. Cracking the context-specific PI3K signaling code. Sci. Signal. https://doi.org/10.1126/scisignal.aay2940 (2020).

    Article  PubMed  Google Scholar 

  141. Madsen, R. R., Vanhaesebroeck, B. & Semple, R. K. Cancer-associated PIK3CA mutations in overgrowth disorders. Trends Mol. Med. 24, 856–870 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Venot, Q. et al. Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature 558, 540–546 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Yu, K. et al. PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis. Nature 578, 166–171 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Goncalves, M. D., Hopkins, B. D. & Cantley, L. C. Phosphatidylinositol 3-kinase, growth disorders, and cancer. N. Engl. J. Med. 379, 2052–2062 (2018).

    Article  CAS  PubMed  Google Scholar 

  145. Turner, N. C. et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N. Engl. J. Med. 379, 1926–1936 (2018).

    Article  CAS  PubMed  Google Scholar 

  146. 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 

  147. Rugo, H. S. et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 22, 489–498 (2021).

    Article  CAS  PubMed  Google Scholar 

  148. Vora, S. R. et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 26, 136–149 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Diehl, J. A., Cheng, M., Roussel, M. F. & Sherr, C. J. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12, 3499–3511 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Pascual, J. et al. Triplet therapy with palbociclib, taselisib, and fulvestrant in PIK3CA-mutant breast cancer and doublet palbociclib and taselisib in pathway-mutant solid cancers. Cancer Discov. 11, 92–107 (2021).

    Article  CAS  PubMed  Google Scholar 

  151. Bardia, A. et al. Phase I/II trial of exemestane, ribociclib, and everolimus in women with HR+/HER2 advanced breast cancer after progression on CDK4/6 inhibitors (TRINITI-1). Clin. Cancer Res. 27, 4177–4185 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Bardia, A. et al. Phase Ib dose-escalation/expansion trial of ribociclib in combination with everolimus and exemestane in postmenopausal women with HR+, HER2 advanced breast cancer. Clin. Cancer Res. 26, 6417–6428 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Hanker, A. B. et al. Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies. Proc. Natl Acad. Sci. USA 110, 14372–14377 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Baselga, J. et al. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J. Clin. Oncol. 32, 3753–3761 (2014).

    Article  CAS  PubMed  Google Scholar 

  155. Baselga, J. et al. Relationship between tumor biomarkers and efficacy in EMILIA, a phase III study of trastuzumab emtansine in HER2-positive metastatic breast cancer. Clin. Cancer Res. 22, 3755–3763 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Jain, S. et al. Phase I study of alpelisib (BYL-719) and trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC) after trastuzumab and taxane therapy. Breast Cancer Res. Treat. 171, 371–381 (2018).

    Article  CAS  PubMed  Google Scholar 

  157. Jhaveri, K. et al. A phase I study of alpelisib in combination with trastuzumab and LJM716 in patients with PIK3CA-mutated HER2-positive metastatic breast cancer. Clin. Cancer Res. 27, 3867–3875 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Dunn, L. A. et al. A phase 1b study of cetuximab and BYL719 (Alpelisib) concurrent with intensity modulated radiation therapy in stage III-IVB head and neck squamous cell carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 106, 564–570 (2020).

    Article  CAS  PubMed  Google Scholar 

  159. Ibrahim, Y. H. et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov. 2, 1036–1047 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Juvekar, A. et al. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov. 2, 1048–1063 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Gonzalez-Billalabeitia, E. et al. Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. Cancer Discov. 4, 896–904 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Cardnell, R. J. et al. Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer. Clin. Cancer Res. 19, 6322–6328 (2013).

    Article  CAS  PubMed  Google Scholar 

  163. Matulonis, U. A. et al. Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer. Ann. Oncol. 28, 512–518 (2017).

    Article  CAS  PubMed  Google Scholar 

  164. Konstantinopoulos, P. A. et al. Olaparib and alpha-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial. Lancet Oncol. 20, 570–580 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Batalini, F. et al. Phase 1b clinical trial with alpelisib plus olaparib for patients with advanced triple-negative breast cancer. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-21-3045 (2022).

    Article  PubMed  Google Scholar 

  166. Nelson, A. C. et al. AKT regulates BRCA1 stability in response to hormone signaling. Mol. Cell Endocrinol. 319, 129–142 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Xiang, T. et al. Negative regulation of AKT activation by BRCA1. Cancer Res. 68, 10040–10044 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Razavi, P. et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell 34, 427–438.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Mundt, F. et al. Mass spectrometry-based proteomics reveals potential roles of NEK9 and MAP2K4 in resistance to pi3k inhibition in triple-negative breast cancers. Cancer Res. 78, 2732–2746 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Ellis, M. J. et al. Connecting genomic alterations to cancer biology with proteomics: the NCI clinical proteomic tumor analysis consortium. Cancer Discov. 3, 1108–1112 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Edwards, N. J. et al. The CPTAC data portal: a resource for cancer proteomics research. J. Proteome Res. 14, 2707–2713 (2015).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge the many seminal papers on this subject that they could not discuss and cite owing to space and editorial limits. The authors acknowledge support from the NIH (grants K08 CA245192 to N.V. and R35 CA197588 to L.C.C.) and the Susan G. Komen Breast Cancer Foundation (to N.V.).

Author information

Authors and Affiliations

Authors

Contributions

Both authors contributed to all aspects of the preparation of this manuscript.

Corresponding author

Correspondence to Lewis C. Cantley.

Ethics declarations

Competing interests

N.V. reports consulting activities for Novartis and is on the scientific advisory board of Heligenics. L.C.C. is a founder, shareholder and member of the scientific advisory board of Agios Pharmaceuticals, a co-founder and shareholder of Faeth Therapeutics, and a founder and former member of the scientific advisory board of Ravenna Pharmaceuticals (previously Petra Pharmaceuticals); these companies are all developing therapies for cancer. L.C.C. has also received research funding from Ravenna Pharmaceuticals.

Peer review

Peer review information

Nature Reviews Clinical Oncology thanks C. L. Arteaga, E. Hirsch and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

4OVU: https://www.rcsb.org/structure/4ovu

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Vasan, N., Cantley, L.C. At a crossroads: how to translate the roles of PI3K in oncogenic and metabolic signalling into improvements in cancer therapy. Nat Rev Clin Oncol 19, 471–485 (2022). https://doi.org/10.1038/s41571-022-00633-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-022-00633-1

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer