TY - JOUR
T1 - ONC201 shows potent anticancer activity against medullary thyroid cancer via transcriptional inhibition of RET, VEGFR2, and IGFBP2
AU - Bagheri-Yarmand, Rozita
AU - Dadu, Ramona
AU - Ye, Lei
AU - Jebaraj, Yaashmin Shiny
AU - Martinez, Jade A.
AU - Ma, Junsheng
AU - Tarapore, Rohinton S.
AU - Allen, Joshua E.
AU - Sherman, Steven I.
AU - Williams, Michelle D.
AU - Gagel, Robert F.
N1 - Funding Information:
This work was supported by the NIH through grants P50CA168505/DRP (to R. Bagheri-Yarmand) and used RPPA-functional proteomics, flowcytometry and cellular imaging, cytogenetics and cell authentication, and cell research histology cores that are supported by the Cancer Center Support Grant (P30CA01667).
Funding Information:
R. Dadu reported grants from Exelixis, Eisai, Merck, and AstraZeneca; in addition, R. Dadu reported personal fees from Exelixis and personal fees from Bayer outside the submitted work. R.S. Tarapore is an employee and stockholder of Oncoceutics that has provided the research material ONC201. J.E. Allen reported nonfinancial support and other from Oncoceutics during the conduct of the study; in addition, J.E. Allen had a patent for ONC201 and derivatives pending, issued, licensed, and with royalties paid from Oncoceutics. M.D. Williams reported grants from NIH during the conduct of the study. R.F. Gagel reported other from Novo Nordisk outside the submitted work. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021
Y1 - 2021
N2 - Gain-of-function point mutations in the receptor tyrosine kinase RET, a driver oncogene in medullary thyroid carcinoma (MTC), prevent apoptosis through inhibition of ATF4, a critical transcriptional regulator of endoplasmic reticulum stress. However, the critical regulatory mechanisms driving RET-dependent oncogene-sis remain elusive, and there is a clinical need to identify a transcriptional RET inhibitor. Here, we found that RET depletion decreased IGFBP2 and VEGFR2 mRNA and protein expression in MTC cells. IGFBP2 knockdown decreased cell survival and migration of MTC cells. In patients, IGFBP2 expression increased in metastatic MTC, and high IGFBP2 associated with poor overall survival. VEGFR2 protein levels were positively associated with RET expression in primary tumors, and VEGF-mediated increased cell viability was RET dependent. The small-molecule ONC201 treatment of MTC cells caused apoptotic cell death, decreased transcription of RET, VEGFR2, IGFBP2, increased mRNA levels of ATF4, and ATF4 target genes including DDIT3, BBC3, DUSP8, MKNK2, KLF9, LZTFL1, and SESN2. Moreover, IGFBP2 depletion increased ONC201-induced cell death. ONC201 inhibited tumor growth at a well-tolerated dose of 120 mg/kg/week administered by oral gavage and decreased MTC xenograft cell proliferation and angiogenesis. The protein levels of RET, IGFBP2, and VEGFR2 were decreased in ONC201-treated xenografts. Our study uncovered a novel ONC201 mechanism of action through regulation of RET and its targets, VEGFR2 and IGFBP2; this mechanism could be translated into the clinic and represent a promising strategy for the treatment of all patients with MTC, including those with TKI-refractory disease and other cancer with RET abnormalities.
AB - Gain-of-function point mutations in the receptor tyrosine kinase RET, a driver oncogene in medullary thyroid carcinoma (MTC), prevent apoptosis through inhibition of ATF4, a critical transcriptional regulator of endoplasmic reticulum stress. However, the critical regulatory mechanisms driving RET-dependent oncogene-sis remain elusive, and there is a clinical need to identify a transcriptional RET inhibitor. Here, we found that RET depletion decreased IGFBP2 and VEGFR2 mRNA and protein expression in MTC cells. IGFBP2 knockdown decreased cell survival and migration of MTC cells. In patients, IGFBP2 expression increased in metastatic MTC, and high IGFBP2 associated with poor overall survival. VEGFR2 protein levels were positively associated with RET expression in primary tumors, and VEGF-mediated increased cell viability was RET dependent. The small-molecule ONC201 treatment of MTC cells caused apoptotic cell death, decreased transcription of RET, VEGFR2, IGFBP2, increased mRNA levels of ATF4, and ATF4 target genes including DDIT3, BBC3, DUSP8, MKNK2, KLF9, LZTFL1, and SESN2. Moreover, IGFBP2 depletion increased ONC201-induced cell death. ONC201 inhibited tumor growth at a well-tolerated dose of 120 mg/kg/week administered by oral gavage and decreased MTC xenograft cell proliferation and angiogenesis. The protein levels of RET, IGFBP2, and VEGFR2 were decreased in ONC201-treated xenografts. Our study uncovered a novel ONC201 mechanism of action through regulation of RET and its targets, VEGFR2 and IGFBP2; this mechanism could be translated into the clinic and represent a promising strategy for the treatment of all patients with MTC, including those with TKI-refractory disease and other cancer with RET abnormalities.
UR - http://www.scopus.com/inward/record.url?scp=85103862577&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85103862577&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-20-0386
DO - 10.1158/1535-7163.MCT-20-0386
M3 - Article
C2 - 33536187
AN - SCOPUS:85103862577
SN - 1535-7163
VL - 20
SP - 665
EP - 675
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 4
ER -