The combination of everolimus and terameprocol exerts synergistic antiproliferative effects in endometrial cancer: molecular role of insulin-like growth factor binding protein 2
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Oncogenic PIK3CA mutations are common in endometrial cancers, and the PI3K/AKT/mTOR pathway is targetable by drugs. We sought to investigate whether the combination of an mTOR inhibitor, everolimus (RAD001), and an AKT inhibitor, terameprocol (M4N), exerts better antiproliferative effects in endometrial cancer. The molecular mechanisms underlying their pharmacological action were also examined. The combination of RAD001 and M4N exerted in vitro synergistic effects on cell viability, apoptosis, and expression of IGFBP2 in endometrial cancer cells. Mechanistically, the Sp1 site on the IGFBP2 promoter was required for RAD001- and M4N-induced downregulation. IGFBP2 protein expression was higher in endometrial cancer than in the normal endometrium (P < 0.001). Furthermore, elevated IGFBP2 histoscores were significantly associated with a lower overall survival (P = 0.021). In conclusion, our in vitro results demonstrate that RAD001 and M4N exert synergistic antiproliferative effects against endometrial cancer cells, which appeared to be mediated by the inhibition of IGFBP2, a key anti-apoptotic regulator. Further clinical studies of this drug combination in patients with endometrial cancer may be warranted, especially in the presence of PIK3CA and IGFBP2 aberrations.
RAD001 and M4N synergistically suppress endometrial cancer growth.
IGFBP2 is overexpressed in endometrial cancer.
The combination of RAD001 and M4N significantly reduces IGFBP2 overexpression.
Sp1 binding site on the IGFBP2 promoter is required for RAD001- and M4N-induced downregulation.
High IGFBP2 histoscore in endometrial cancer portends a poor prognosis.
KeywordsEverolimus Terameprocol Endometrial cancer Insulin-like growth factor binding protein 2
We are grateful to Ms. Jung-Erh Yang for her excellent technical assistance. Formalin-fixed paraffin-embedded specimens were kindly provided by the Tumor Bank. We also acknowledge the statistical assistance provided by the Clinical Trial Center (Chang Gung Memorial Hospital, Linkou, Taiwan), which was founded by the Taiwanese Ministry of Health and Welfare (grant MOHW106-TDU-B-212-113005).
This study was financially supported by grants from the Chang Gung Foundation (CMRPG3C1351/2/3, CMRPG3G1781, CRRPG3D0041-3, and CMRPG3F2111/2) and the Ministry of Science and Technology (MOST 105-2320-B-182A-005).
Compliance with ethical standards
Conflict of interest
SJC is an employee of ACT Genomics Co., Ltd.
- 1.Jemal A, Ward EM, Johnson CJ, Cronin KA, Ma J, Ryerson B, Mariotto A, Lake AJ, Wilson R, Sherman RL et al (2017) Annual report to the nation on the status of cancer, 1975–2014, featuring survival. J Natl Cancer Inst 1:109(9)Google Scholar
- 2.Cancer Registry Annual Report, 2014 Taiwan: Ministry of Health and Welfare, Executive Yuan 2016 https://www.hpa.gov.tw/BHPNet/English/Index.aspx
- 3.Creasman WT, Miller DS (2012) Adenocarcinoma of the uterine corpus. In: Di Saia PJ, Creasman WT, Mannel RS, McMeekin DS, Mutch DG (eds) Clinical gynecologic oncology. Elsevier, Philadelphia, pp 121–154Google Scholar
- 7.Salvesen HB, Carter SL, Mannelqvist M, Dutt A, Getz G, Stefansson IM, Raeder MB, Sos ML, Engelsen IB, Trovik J, Wik E, Greulich H, Bo TH, Jonassen I, Thomas RK, Zander T, Garraway LA, Oyan AM, Sellers WR, Kalland KH, Meyerson M, Akslen LA, Beroukhim R (2009) Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation. Proc Natl Acad Sci U S A 106:4834–4839CrossRefGoogle Scholar
- 13.Ray-Coquard I, Favier L, Weber B, Roemer-Becuwe C, Bougnoux P, Fabbro M, Floquet A, Joly F, Plantade A, Paraiso D, Pujade-Lauraine E (2013) Everolimus as second- or third-line treatment of advanced endometrial cancer: ENDORAD, a phase II trial of GINECO. Br J Cancer 108:1771–1777CrossRefGoogle Scholar
- 23.Zhao S, Choi M, Overton JD, Bellone S, Roque DM, Cocco E, Guzzo F, English DP, Varughese J, Gasparrini S, Bortolomai I, Buza N, Hui P, Abu-Khalaf M, Ravaggi A, Bignotti E, Bandiera E, Romani C, Todeschini P, Tassi R, Zanotti L, Carrara L, Pecorelli S, Silasi DA, Ratner E, Azodi M, Schwartz PE, Rutherford TJ, Stiegler AL, Mane S, Boggon TJ, Schlessinger J, Lifton RP, Santin AD (2013) Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. Proc Natl Acad Sci U S A 110:2916–2921CrossRefGoogle Scholar
- 24.Li Y, Yang X, Su LJ, Flaig TW (2011) Pazopanib synergizes with docetaxel in the treatment of bladder cancer cells. Urology 78(233):e237–e213Google Scholar
- 28.USFDA (2005) Guidance for industry: estimating the maximum safe starting dose in adult healthy volunteer. US Food and Drug Administration, Rockville, MDGoogle Scholar
- 36.Oh SH, Jin Q, Kim ES, Khuri FR, Lee HY (2008) Insulin-like growth factor-I receptor signaling pathway induces resistance to the apoptotic activities of SCH66336 (lonafarnib) through Akt/mammalian target of rapamycin-mediated increases in survivin expression. Clin Cancer Res 14:1581–1589CrossRefGoogle Scholar
- 38.Thul PJ, Akesson L, Wiking M, Mahdessian D, Geladaki A, Ait Blal H, Alm T, Asplund A, Bjork L, Breckels LM et al (2017) A subcellular map of the human proteome. Science:356Google Scholar
- 42.Slomovitz BM, Lu KH, Johnston T, Coleman RL, Munsell M, Broaddus RR, Walker C, Ramondetta LM, Burke TW, Gershenson DM, Wolf J (2010) A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma. Cancer 116:5415–5419CrossRefGoogle Scholar