Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways.
Animals
Cell Cycle
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Drug Synergism
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Isotretinoin
/ administration & dosage
Mice
Mitogen-Activated Protein Kinases
/ metabolism
Neuroblastoma
/ drug therapy
Phenylurea Compounds
/ administration & dosage
Phosphatidylinositol 3-Kinases
/ metabolism
Protein Kinase Inhibitors
/ administration & dosage
Proto-Oncogene Proteins c-akt
/ metabolism
Proto-Oncogene Proteins c-fos
/ metabolism
Proto-Oncogene Proteins c-jun
/ metabolism
Pyridines
/ administration & dosage
Signal Transduction
/ drug effects
TOR Serine-Threonine Kinases
/ metabolism
Xenograft Model Antitumor Assays
ras Proteins
/ metabolism
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
25
09
2019
accepted:
29
04
2020
revised:
26
03
2020
pubmed:
28
5
2020
medline:
26
2
2021
entrez:
28
5
2020
Statut:
ppublish
Résumé
Regorafenib is an inhibitor of multiple kinases with aberrant expression and activity in neuroblastoma tumours that have potential roles in neuroblastoma pathogenesis. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32457362
doi: 10.1038/s41416-020-0905-8
pii: 10.1038/s41416-020-0905-8
pmc: PMC7434894
doi:
Substances chimiques
FOS protein, human
0
Phenylurea Compounds
0
Protein Kinase Inhibitors
0
Proto-Oncogene Proteins c-fos
0
Proto-Oncogene Proteins c-jun
0
Pyridines
0
regorafenib
24T2A1DOYB
MTOR protein, human
EC 2.7.1.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Mitogen-Activated Protein Kinases
EC 2.7.11.24
ras Proteins
EC 3.6.5.2
Isotretinoin
EH28UP18IF
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
568-579Subventions
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Références
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).
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).
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: 15087949
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: 21768459
pmcid: 3158599
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).
pubmed: 28885700
pmcid: 5716896
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).
pubmed: 7524740
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).
pubmed: 10815914
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).
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).
pubmed: 19417027
pmcid: 4238907
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).
pubmed: 7629887
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).
pubmed: 8376577
pmcid: 288252
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: 17941064
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).
pubmed: 10448297
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).
pubmed: 10842244
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).
pubmed: 11912515
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).
pubmed: 15342394
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).
pubmed: 16267010
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).
pubmed: 20564646
pmcid: 2923448
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).
pubmed: 21203803
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: 19939254
pmcid: 2790467
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).
pubmed: 21170960
FDA approves regorafenib (Stivarga) for metastatic colorectal cancer. Oncology 26, 896 (2012).
FDA approves regorafenib (Stivarga) for GIST. Oncology 27, 164 (2013).
Regorafenib approved for liver cancer. Cancer Discov 7, 660 (2017).
Strumberg, D. & Schultheis, B. Regorafenib for cancer. Expert Opin. Investig. Drugs 21, 879–889 (2012).
pubmed: 22577890
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: 26599335
pmcid: 4658168
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: 26925841
pmcid: 4772351
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).
pubmed: 24832869
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).
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: 25222284
pmcid: 4164617
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: 31695841
pmcid: 6824878
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).
pubmed: 24011073
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).
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).
pubmed: 27586230
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).
pubmed: 19171716
pmcid: 2738615
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).
pubmed: 20225331
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).
pubmed: 8195928
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).
pubmed: 9605760
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).
pubmed: 8439501
pmcid: 1968281
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).
pubmed: 9393766
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).
pubmed: 11768614
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).
pubmed: 14709738
Schubbert, S., Shannon, K. & Bollag, G. Hyperactive ras in developmental disorders and cancer. Nat. Rev. Cancer 7, 295–308 (2007).
pubmed: 17384584
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).
pubmed: 22142829
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).
pubmed: 23334666
pmcid: 3682833
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).
pubmed: 26121087
pmcid: 4775079
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).
pubmed: 25811750
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: 28582410
pmcid: 5459446
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).
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).
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).
pubmed: 27649927
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).
pubmed: 21690471
pmcid: 3138720
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).
pubmed: 27357360
pmcid: 5021041
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: 26696630
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).
pubmed: 24347491
pmcid: 4277327
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).
pubmed: 23169148
pmcid: 3582757
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).
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: 29262623
pmcid: 5732789
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).
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: 28842575
pmcid: 5573380
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).
pubmed: 22421192
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).
pubmed: 22568966
pmcid: 3364125
Miller, W. H. The emerging role of retinoids and retinoic acid metabolism blocking agents in the treatment of cancer. Cancer 83, 1471–1482 (1998).
pubmed: 9781940
Sidell, N. Retinoic acid-induced growth inhibition and morphologic differentiation of human neuroblastoma cells in vitro. J. Natl Cancer Inst. 68, 589–596 (1982).
pubmed: 7040765
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).
pubmed: 6313408
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).
pubmed: 3855502
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).
pubmed: 7867726
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).
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).
pubmed: 17431108
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).
pubmed: 10936180
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).
pubmed: 11464863