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Translational Therapeutics

Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways

British Journal of Cancer volume 123, pages568–579(2020)Cite this article

Subjects

Abstract

Background

Regorafenib is an inhibitor of multiple kinases with aberrant expression and activity in neuroblastoma tumours that have potential roles in neuroblastoma pathogenesis.

Methods

We evaluated neuroblastoma cells treated with regorafenib for cell viability and confluence, and analysed treated cells for apoptosis and cell cycle progression. We evaluated the efficacy of regorafenib in vivo using an orthotopic xenograft model. We evaluated regorafenib-mediated inhibition of kinase targets and performed reverse-phase protein array (RPPA) analysis of neuroblastoma cells treated with regorafenib. Lastly, we evaluated the efficacy and effects of the combination of regorafenib and 13-cis-retinoic acid on intracellular signalling.

Results

Regorafenib treatment resulted in reduced neuroblastoma cell viability and confluence, with both induction of apoptosis and of cell cycle arrest. Regorafenib treatment inhibits known receptor tyrosine kinase targets RET and PDGFRβ and intracellular signalling through the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. Regorafenib is effective against neuroblastoma tumours in vivo, and the combination of regorafenib and 13-cis-retinoic acid demonstrates enhanced efficacy compared with regorafenib alone.

Conclusions

The effects of regorafenib on multiple intracellular signalling pathways and the potential additional efficacy when combined with 13-cis-retinoic acid represent opportunities to develop treatment regimens incorporating regorafenib for children with neuroblastoma.

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Fig. 1: Regorafenib reduces neuroblastoma cell viability and xenograft tumour growth.
Fig. 2: Regorafenib induces neuroblastoma cell apoptosis.
Fig. 3: Regorafenib inhibits targets in neuroblastoma cells.
Fig. 4: Regorafenib treatment alters protein expression and phosphorylation in neuroblastoma cells.
Fig. 5: Efficacy of regorafenib combined with 13-cis-retinoic acid in neuroblastoma cells.
Fig. 6: Regorafenib combined with 13-cis-retinoic acid alters protein expression and phosphorylation in neuroblastoma cells.

References

  1. 1.

    Matthay, K. K., Maris, J. M., Schleiemacher, G., Nakagawara, A., Mackall, C. L. Diller, L. et al. Neuroblastoma. Nat. Rev. Dis. Prim. 2, 1–21 (2016).

    Google Scholar 

  2. 2.

    Whittle, S. B., Smith, V., Doherty, E., Zhao, S., McCarty, S. & Zage, P. E. Overview and recent advances in the treatment of neuroblastoma. Exp. Rev. Anticancer Ther. 17, 369–386 (2017).

    CAS  Google Scholar 

  3. 3.

    Lau, L., Tai, D., Weitzman, S., Grant, R., Baruchel, S. & Malkin, D. Factors influencing survival in children with recurrent neuroblastoma. J. Pediatr. Hematol. Oncol. 26, 227–232 (2004).

    PubMed  Google Scholar 

  4. 4.

    London, W. B., Castel, V., Monclair, T., Ambros, P. F., Pearson, A. D. J., Cohn, S. L. et al. Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International Neuroblastoma Risk Group Project. J. Clin. Oncol. 29, 3286–3292 (2011).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    London, W. B., Bagatell, R., Weigel, B. J., Fox, E., Guo, D., Van Ryn, C. et al. Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children’s Oncology Group early-phase trials. Cancer 123, 4914–4923 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Cohen, P. S., Chan, J. P., Lipkunskaya, M., Biedler, J. L. & Seeger, R. C. Expression of stem cell factor and c-kit in human neuroblastoma. Blood 84, 3465–3472 (1994).

    CAS  PubMed  Google Scholar 

  7. 7.

    Eggert, A., Ikegaki, N., Kwiatkowski, J., Zhao, H., Brodeur, G. M. & Himelstein, B. P. High-level expression of angiogenic factors is associated with advanced tumor stage in human neuroblastomas. Clin. Cancer Res. 6, 1900–1908 (2000).

    CAS  PubMed  Google Scholar 

  8. 8.

    Meyers, M. B., Shen, W. P., Spengler, B. A., Ciccarone, V., O’Brien, J. P., Donner, D. B. et al. Increased epidermal growth factor receptor in multidrug-resistant human neuroblastoma cells. J. Cell Biochem. 38, 87–97 (1998).

    Google Scholar 

  9. 9.

    Brodeur, G. M., Minturn, J. E., Ho, R., Simpson, A. M., Iyer, R., Varela, C. et al. Trk receptor expression and inhibition in neuroblastoma. Clin. Cancer Res. 15, 3244–3250 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Janet, T., Ludecke, G., Otten, U. & Unsicker, K. Heterogeneity of human neuroblastoma cell lines in their proliferative responses to basic FGF, NGF, and EGF: correlation with expression of growth factors and growth factor receptors. J. Neurosci. Res. 40, 707–715 (1995).

    CAS  PubMed  Google Scholar 

  11. 11.

    Matsui, T., Sano, K., Tsukamoto, T., Ito, M., Takaishi, T., Nakata, H. et al. Human neuroblastoma cells express alpha and beta platelet-derived growth factor receptors coupling with neurotrophic and chemotactic signaling. J. Clin. Invest. 92, 1153–1160 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Shimada, A., Hirato, J., Kuroiwa, M., Kukuchi, A., Hanada, R., Wakai, K. et al. Expression of KIT and PDGFR is associated with a good prognosis in neuroblastoma. Pediatr. Blood Cancer 50, 213–217 (2008).

    PubMed  Google Scholar 

  13. 13.

    Meister, B., Grunebach, F., Bautz, F., Brugger, W., Fink, F. M., Kanz, L. et al. Expression of vascular endothelial growth factor (VEGF) and its receptors in human neuroblastoma. Eur. J. Cancer 35, 445–449 (1999).

    CAS  PubMed  Google Scholar 

  14. 14.

    Langer, I., Vertongen, P., Perret, J., Fontaine, J., Atassi, G. & Robberecht, P. Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in human neuroblastomas. Med. Pediatr. Oncol. 34, 386–393 (2000).

    CAS  PubMed  Google Scholar 

  15. 15.

    Fakhari, M., Pullirsch, D., Paya, K., Abraham, D., Hofbauer, R. & Aharinejad, S. Upregulation of vascular endothelial growth factor receptors is associated with advanced neuroblastoma. J. Pediatr. Surg. 37, 582–587 (2002).

    CAS  PubMed  Google Scholar 

  16. 16.

    Hecht, M., Papoutsi, M., Tran, H. D., Wilting, J. & Schweigerer, L. Hepatocyte growth factor/c-Met signaling promotes the progression of experimental human neuroblastomas. Cancer Res. 64, 6109–6118 (2004).

    CAS  PubMed  Google Scholar 

  17. 17.

    Ho, R., Minturn, J. E., Hishiki, T., Zhao, H., Wang, Q., Cnaan, A. et al. Proliferation of human neuroblastomas mediated by the epidermal growth factor receptor. Cancer Res. 65, 9868–9875 (2005).

    CAS  PubMed  Google Scholar 

  18. 18.

    Richards, K. N., Zweidler-McKay, P. A., Van Roy, N., Speleman, F., Trevino, J., Zage, P. E. et al. Signaling of ERBB receptor tyrosine kinases promotes neuroblastoma growth in vitro and in vivo. Cancer 116, 3233–3243 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Izycka-Swieszewska, E., Wozniak, A., Drozynska, E., Kot, J., Grajkowska, W., Klepacka, T. et al. Expression and significance of HER family receptors in neuroblastic tumors. Clin. Exp. Metastasis 28, 271–282 (2011).

    CAS  PubMed  Google Scholar 

  20. 20.

    Crosswell, H. E., Dasgupta, A., Alvarado, C. S., Watt, T., Christensen, J. G., De, P. et al. PHA665752, a small-molecule inhibitor of c-Met, inhibits hepatocyte growth factor-stimulated migration and proliferation of c-Met-positive neuroblastoma cells. BMC Cancer 9, 411 (2009).

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Wilhelm, S. M., Dumas, J., Adnane, L., Lynch, M., Carter, C. A., Schütz, G. et al. Regorafenib (BAY 73–4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J. Cancer 129, 245–255 (2011).

    CAS  PubMed  Google Scholar 

  22. 22.

    FDA approves regorafenib (Stivarga) for metastatic colorectal cancer. Oncology 26, 896 (2012).

  23. 23.

    FDA approves regorafenib (Stivarga) for GIST. Oncology 27, 164 (2013).

  24. 24.

    Regorafenib approved for liver cancer. Cancer Discov 7, 660 (2017).

  25. 25.

    Strumberg, D. & Schultheis, B. Regorafenib for cancer. Expert Opin. Investig. Drugs 21, 879–889 (2012).

    CAS  PubMed  Google Scholar 

  26. 26.

    Daudigeos-Dubus, E., Le Dret, L., Lanvers-Kaminsky, C., Bawa, O., Opolon, P., Vievard, A. et al. Regorafenib: antitumor activity upon mono and combination therapy in preclinical pediatric malignancy models. PLoS ONE 10, e0142612 (2015).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Woodfield, S. E., Zhang, L., Scorsone, K., Liu, Y. & Zage, P. E. Binimetinib Inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression. BMC Cancer 16, 172 (2016).

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Scorsone, K., Zhang, L., Woodfield, S. E., Hicks, J. & Zage, P. E. The novel kinase inhibitor EMD1214063 is effective against neuroblastoma. Invest New Drugs 32, 815–824 (2014).

    CAS  PubMed  Google Scholar 

  29. 29.

    Zhang, L., Scorsone, K., Woodfield, S. E. & Zage, P. E. Sensitivity of neuroblastoma to the novel kinase inhibitor cabozantinib is mediated by ERK inhibition. Cancer Chemother. Pharm. 76, 977–987 (2015).

    CAS  Google Scholar 

  30. 30.

    Schneider, M. J., Cyran, C. C., Nikolaou, K., Hirner, H., Reiser, M. F. & Dietrich, O. Monitoring early response to anti-angiogenic therapy: diffusion-weighted magnetic resonance imaging and volume measurements in colon carcinoma xenografts. PLos ONE 9, e106970 (2014).

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Flynn, S., Lesperance, J., Macias, A., Phanhthilath, N., Paul, M. R., Kim, J. W. et al. The Multikinase Inhibitor RXDX-105 is effective against neuroblastoma in vitro and in vivo. Oncotarget 10, 6323–6333 (2019).

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Dong, S., Jia, C., Zhang, S., Fan, G., Li, Y., Shan, P. et al. The REGγ proteasome regulates hepatic lipid metabolism through inhibition of autophagy. Cell Metab. 18, 380–391 (2013).

    CAS  PubMed  Google Scholar 

  33. 33.

    Chang, C. H., Zhang, M., Rajapakshe, K., Coarfa, C., Edwards, D., Huang, S. et al. Mammary stem cells and tumor-initiating cells are more resistant to apoptosis and exhibit increased DNA repair activity in response to DNA damage. Stem Cell Rep. 5, 378–391 (2015).

    CAS  Google Scholar 

  34. 34.

    Whittle, S. B., Patel, K., Zhang, L., Woodfied, S. E., Du, M., Smith, V. et al. The novel kinase inhibitor ponatinib is an effective anti-angiogenic agent against neuroblastoma. Invest New Drugs 34, 685–692 (2016).

    CAS  PubMed  Google Scholar 

  35. 35.

    Matthay, K. K., Reynolds, C. P., Seeger, R. C., Shimada, H., Adkins, E. S., Haas-Kogan D. et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: A Children’s Oncology Group Study. J. Clin. Oncol. 27, 1007–1013 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Zage, P. E., Zeng, L., Palla, S., Fang, W., Nilsson, M. B., Heymach, J. V. et al. A novel therapeutic combination for neuroblastoma: the VEGFR/EGFR/RET inhibitor vandetanib with 13-cis-retinoic acid. Cancer 116, 2465–2475 (2010).

    CAS  PubMed  Google Scholar 

  37. 37.

    Nakamura, T., Ishizaka, Y., Nagao, M., Hara, M. & Ishikawa, T. Expression of the ret proto-oncogene product in human normal and neoplastic tissues of neural crest origin. J. Pathol. 172, 255–260 (1994).

    CAS  PubMed  Google Scholar 

  38. 38.

    Hishiki, T., Nimura, Y., Isogai, E., Kondo, K., Ichimiya, S., Nakamura, Y. et al. Glial cell line-derived neurotrophic factor/neurturin-induced differentiation and its enhancement by retinoic acid in primary human neuroblastomas expressing c-Ret, GFR alpha-1, and GFR alpha-2. Cancer Res. 58, 2158–2165 (1998).

    CAS  PubMed  Google Scholar 

  39. 39.

    Iwamoto, T., Taniguchi, M., Wajjwalku, W., Nakashima, I. & Takahashi, M. Neuroblastoma in a transgenic mouse carrying a metallothionein/ret fusion gene. Br. J. Cancer 67, 504–507 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Marshall, G. M., Peaston, A. E., Hocker, J. E., Smith, S. A., Hansford, L. M., Tobias, V. et al. Expression of multiple endocrine neoplasia 2B RET in neuroblastoma cells alters cell adhesion in vitro, enhances metastatic behavior in vivo, and activates jun kinase. Cancer Res. 57, 5399–5405 (1997).

    CAS  PubMed  Google Scholar 

  41. 41.

    Komuro, H., Kaneko, S., Kaneko, M. & Nakanishi, Y. Expression of angiogenic factors and tumor progression in human neuroblastoma. J. Cancer Res. Clin. Oncol. 127, 739–743 (2001).

    CAS  PubMed  Google Scholar 

  42. 42.

    Beppu, K., Jaboine, J., Merchant, M. S., Mackall, C. L. & Thiele, C. J. Effect of imatinib mesylate on neuroblastoma tumorigenesis and vascular endothelial growth factor expression. J. Natl Cancer Inst. 96, 46–55 (2004).

    CAS  PubMed  Google Scholar 

  43. 43.

    Schubbert, S., Shannon, K. & Bollag, G. Hyperactive ras in developmental disorders and cancer. Nat. Rev. Cancer 7, 295–308 (2007).

    CAS  PubMed  Google Scholar 

  44. 44.

    Shukla, N., Ameur, N., Yilmaz, I., Nafa, K., Lau, C. Y., Marchetti, A. et al. Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways. Clin. Cancer Res. 18, 748–757 (2012).

    CAS  PubMed  Google Scholar 

  45. 45.

    Pugh, T. J., Morozova, O., Attiyeh, E. F., Asgharzadeh, S., Wei, J. S., Auclair, D. et al. The Genetic Landscape of High-Risk Neuroblastoma. Nat. Genet. 45, 279–284 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Eleveld, T. F., Oldridge, D. A., Bernard, V., Koster, J., Daage, L. C., Diskin, S. J. et al. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat. Genet 47, 864–871 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    King, D., Yeomanson, D. & Bryant, H. E. PI3King the lock: targeting the PI3K/Akt/mTOR pathway as a novel therapeutic strategy in neuroblastoma. J. Pediatr. Hematol. Oncol. 37, 245–251 (2015).

    CAS  PubMed  Google Scholar 

  48. 48.

    Becher, O. J., Millard, N. E., Modak, S., Kushner, B. H., Haque, S., Spasojevic, I. et al. A phase I study of single-agent perifosine for recurrent or refractory pediatric CNS and solid tumors. PLoS ONE 12, e0178593 (2017).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Matsumoto, K., Shichino, H., Kawamoto, H., Kosaka, Y., Chin, M., Kato, K. et al. Phase I study of perifosine monotherapy in patients with recurrent or refractory neuroblastoma. Pediatr. Blood Cancer 64, e26623 (2017).

    Google Scholar 

  50. 50.

    Becher, O. J., Gilheeney, S. W., Khakoo, Y., Lyden, D. C., Haque, S., De Braganca, K. C. et al. A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors. Pediatr. Blood Cancer 64, e26409 (2017).

    Google Scholar 

  51. 51.

    Kushner, B. H., Cheung, N. V., Modak, S., Becher, O. J., Basu, E. M., Roberts, S. S. et al. A phase I/Ib trial targeting the Pi3k/Akt pathway using perifosine: Long-term progression-free survival of patients with resistant neuroblastoma. Int J. Cancer 140, 480–484 (2017).

    CAS  PubMed  Google Scholar 

  52. 52.

    Spunt, S. L., Grupp, S. A., Vik, T. A., Santana, V. M., Greenblatt, D. J., Clancy, J. et al. Phase I study of temsirolimus in pediatric patients with recurrent/refractory solid tumors. J. Clin. Oncol. 29, 2933–2940 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Sheikh, A., Takatori, A., Hossain, M. S., Hasan, M. K., Tagawa, M., Nagase, H. et al. Unfavorable neuroblastoma prognostic factor NLRR2 inhibits cell differentiation by transcriptional induction through JNK pathway. Cancer Sci. 107, 1223–1223 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Fey, D., Halasz, M., Dreidax, D., Kennedy, S. P., Hastings, J. F., Rauch, N. et al. Signaling pathway models as biomarkers: patient-specific simulations of JNK activity predict the survival of neuroblastoma patients. Sci. Signal 8, ra130 (2015).

    PubMed  Google Scholar 

  55. 55.

    Schmieder, R., Hoffmann, J., Becker, M., Bhargava, A., Müller, T., Kahmann, N. et al. Regorafenib (BAY 73–4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer. Int J. Cancer 135, 1487–1496 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Carr, B. I., D’Alessandro, R., Refolo, M. G., Iacovazzi, P. A., Lippolis, C., Messa, C. et al. Effects of low concentrations of regorafenib and sorafenib on human HCC cell AFP, migration, invasion and growth in vitro. J. Cell Physiol. 228, 1344–1350 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    D’Alessandro, R., Refolo, M. G., Lippolis, C., Messa, C., Cavallini, A., Rossi, R. et al. Reversibility of regorafenib effects in hepatocellular carcinoma cells. Cancer Chemother. Pharm. 72, 869–877 (2013).

    Google Scholar 

  58. 58.

    Chen, Z., Zhao, Y., Yu, Y., Pang, J. C., Woodfield, S. E., Tao, L. et al. Small molecule inhibitor regorafenib inhibits RET signaling in neuroblastoma cells and effectively suppresses tumor growth in vivo. Oncotarget 8, 104090–104103 (2017).

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Krishnamoorthy, S. K., Relias, V., Sebastian, S., Jayaraman, V. & Said, M. W. Management of regorafenib-related toxicities: a review. Ther. Adv. Gastroenterol. 8, 285–297 (2015).

    CAS  Google Scholar 

  60. 60.

    Schvartsman, G., Wagner, M. J., Amini, B., Zobniw, C. M., Trinh, V. A., Barbo, A. G. et al. Treatment patterns, efficacy and toxicity of regorafenib in gastrointestinal stromal tumour patients. Sci. Rep. 7, 9519 (2017).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Mross, K., Frost, A., Steinbild, S., Hadbom, S., Buchert, M., Fasoi, U. et al. A phase I dose-escalation study of regorafenib (BAY 73-4506), an Inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin. Cancer Res. 18, 2658–2667 (2012).

    CAS  PubMed  Google Scholar 

  62. 62.

    Strumberg, D., Scheulen, M. E., Schultheis, B., Richly, H., Frost, A., Buchert, A. et al. Regorafenib (BAY 73-4506) in advanced colorectal cancer: A phase I study. Br. J. Cancer 106, 1722–1727 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Miller, W. H. The emerging role of retinoids and retinoic acid metabolism blocking agents in the treatment of cancer. Cancer 83, 1471–1482 (1998).

    CAS  PubMed  Google Scholar 

  64. 64.

    Sidell, N. Retinoic acid-induced growth inhibition and morphologic differentiation of human neuroblastoma cells in vitro. J. Natl Cancer Inst. 68, 589–596 (1982).

    CAS  PubMed  Google Scholar 

  65. 65.

    Sidell, N., Altman, A., Haussler, M. R. & Seeger, R. C. Effects of retinoic acid (RA) on the growth and phenotypic expression of several human neuroblastoma cell lines. Exp. Cell Res. 148, 21–30 (1983).

    CAS  PubMed  Google Scholar 

  66. 66.

    Thiele, C. J., Reynolds, C. P. & Israel, M. A. Decreased expression of N-myc precedes retinoic acid-induced morphological differentiation of human neuroblastoma. Nature 313, 404–406 (1985).

    CAS  PubMed  Google Scholar 

  67. 67.

    Bunone, G., Borrello, M. G., Picetti, R., Bongarzone, I., Peverali, F. A., de Franciscis, V. et al. Induction of RET proto-oncogene expression in neuroblastoma cells precedes neuronal differentiation and is not mediated by protein synthesis. Exp. Cell Res. 217, 92–99 (1995).

    CAS  PubMed  Google Scholar 

  68. 68.

    D’Aleesio, A., De Vita, G., Cali, G., Nitsch, L., Fusco, A., Vecchio, G. et al. Expression of the RET oncogene induces differentiation of SK-N-BE neuroblastoma cells. Cell Growth Differ. 6, 1387–1394 (1995).

    Google Scholar 

  69. 69.

    Oppenheimer, O., Cheung, N.-K. & Gerald, W. L. The RET oncogene is a critical component of transcriptional programs associated with retinoic acid-induced differentiation in neuroblastoma. Mol. Cancer Ther. 6, 1300–1309 (2007).

    CAS  PubMed  Google Scholar 

  70. 70.

    Encinas, M., Iglesias, M., Liu, Y., Wang, H., Muhaisen, A., Cena, V. et al. Sequential treatment of SH-SY5Y cells with retinoic acid and brain-derived neurotrophic factor gives rise to fully differentiated, neurotrophic factor-dependent, human neuron-like cells. J. Neurochem. 75, 991–1003 (2000).

    CAS  PubMed  Google Scholar 

  71. 71.

    Takada, N., Isogai, E., Kawamoto, Nakanishi, H., Todo, S. & Nakagawara, A. Retinoic acid-induced apoptosis of the CHP134 neuroblastoma cell line is associated with nuclear accumulation of p53 and is rescued by the GDNF/Ret signal. Med. Pediatr. Oncol. 36, 122–126 (2001).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Portions of this work have been published as an abstract (Subramonian et al., J Clin Oncol 2017; 35:10553) and presented as a poster at the American Society of Clinical Oncology Annual Meeting in June of 2017.

Author information

Author notes

  1. Qianxing Mo

    Present address: Department of Biostatistics & Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA

  2. These authors contributed equally: Divya Subramonian, Nikki Phanhthilath

Affiliations

  1. Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego, La Jolla, CA, USA

    Divya Subramonian, Nikki Phanhthilath, Hannah Rinehardt, Sean Flynn, Yuchen Huo, Jacqueline Lesperance & Peter E. Zage

  2. Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA

    Jing Zhang & Karen Messer

  3. Department of Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Qianxing Mo & Shixia Huang

  4. Peckham Center for Cancer and Blood Disorders, Rady Children’s Hospital, San Diego, CA, USA

    Peter E. Zage

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Contributions

D.S.: conceptualisation, data curation, formal analysis, investigation, methodology, validation and writing—review and editing. N.P.: data curation, formal analysis, investigation, validation, writing—original draft and writing—review and editing. H.R.: data curation, investigation, validation and writing—review and editing. S.F.: data curation, investigation, validation and writing—review and editing. Y.H.: data curation, investigation, validation and writing—review and editing. J.Z.: data curation, formal analysis, investigation, validation, writing—original draft and writing—review and editing. K.M.: data curation, formal analysis, investigation, supervision, validation and writing—review and editing. Q.M.: data curation, formal analysis, investigation, validation and writing—review and editing. S.H.: data curation, formal analysis, investigation, supervision, validation and writing—review and editing. J.L.: data curation, investigation, validation and writing—review and editing. P.E.Z.: conceptualisation, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, resources, supervision, validation, writing—original draft and writing—review and editing.

Corresponding author

Correspondence to Peter E. Zage.

Ethics declarations

Ethics approval and consent to participate

All animal experiments were performed in accordance with relevant guidelines and regulations, and all mice were treated according to protocols approved by the Institutional Animal Care and Use Committee at UCSD; no human subjects were included in these experiments.

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Not applicable; no human subjects were included in these experiments.

Data availability

All data generated or analysed during this study are included in this published article (and the Supplementary information files).

Competing interests

This study was supported by Bayer, AG with study drug and research funding (to P.E.Z.). The authors declare there are no other competing interests.

Funding information

This study was supported by Bayer, AG with study drug and research funding (to P.E.Z.). This work was supported in part by a Cancer Prevention & Research Institute of Texas Proteomics & Metabolomics Core Facility Support Award (RP170005) (to S.H.) and an NCI Cancer Center Support Grant to the Antibody-based Proteomics Core/Shared Resource at Baylor College of Medicine (P30CA125123) (to S.H.).

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Subramonian, D., Phanhthilath, N., Rinehardt, H. et al. Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. Br J Cancer 123, 568–579 (2020). https://doi.org/10.1038/s41416-020-0905-8

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