OSI-906 restores the sensitivity of ovarian clear cell carcinoma to cisplatin by targeting the IGF1R/AKT pathway

Abstract

Among the various histologic subtypes of ovarian cancers (OCs), ovarian clear cell carcinoma (OCCC) represents a great challenge due to its disease aggressiveness and resistance to chemotherapy. IGF1 is overexpressed in epithelial ovarian cancer (EOC), and IGF1 pathway activation is related to the chemoresistance of various cancers. In this study, we found that the expression level of IGF1 was higher in OCCC than in the most common type of OC, high-grade serous adenocarcinoma (HGSC). Then, we investigated the role of IGF1 pathway activation in the progression of OCCC, observing that activation of the IGF1 pathway using IGF1 promoted the proliferation and migration of ES2 cells, while inactivation of the IGF1 pathway using the selective IGF1R inhibitor OSI-906 reversed the alteration mediated by IGF1.Based on the role of the IGF1 pathway in cancer chemoresistance, we proposed that OSI-906 may restore the sensitivity of OCCC to cisplatin. We rst validated that IGF1 increased the IC50 value of cisplatin in ES2 cells, while OSI-906 decreased it. Then we con rmed that IGF1 decreased the apoptosis rate of ES2 cells induced by cisplatin, while OSI-906 increased it. Finally, we conducted animal experiments to investigate whether OSI-906 helps cisplatin control the growth of OCCC. As expected, OSI-906 increased the effect of cisplatin in attenuating the growth of OCCC in vivo. Therefore, we conclude that using OSI-906 may be an effective method to restore the sensitivity of OCCC to cisplatin by targeting the IGF1R/AKT pathway.

Insulin-like growth factor-1 signaling in the tumor microenvironment: Carcinogenesis, cancer drug resistance, and therapeutic potential

“…Interestingly, in a recent study using resistant colon cancer stem-like cells and mouse models, combination therapy of regorafenib with two antagonists of IGF-1-R, namely aspirin and the selective dual insulin receptor and IGF-1R kinase inhibitor linsitinib (OSI-906), abrogated tumor resistance to regorafenib and restored the drug’s ability to induce apoptosis in colon cancer stem-like cells and disease activity index ( 51 ). Linsitinib also restored the sensitivity of ovarian clear cell carcinoma (OCCC) cells to the chemotherapy drug cisplatin by silencing the IGF-1R/AKT signaling pathway ( 52 ). Notably, in this study, OCCC which has greater disease aggressiveness and resistance to chemotherapy than epithelial ovarian cancer, the most common type of ovarian cancer, also showed higher levels of IGF-1 ( 52 ).…”

“…Linsitinib also restored the sensitivity of ovarian clear cell carcinoma (OCCC) cells to the chemotherapy drug cisplatin by silencing the IGF-1R/AKT signaling pathway ( 52 ). Notably, in this study, OCCC which has greater disease aggressiveness and resistance to chemotherapy than epithelial ovarian cancer, the most common type of ovarian cancer, also showed higher levels of IGF-1 ( 52 ). These observations indicate that the strength of responses of chemotherapy-resistant cancers to anti-IGF agents will depend on the extent of IGF-1R signaling in tumors.…”

“…The drug candidates targeting IGF-1R signaling that are under clinical trial investigation include: IGF ligand inhibitors, which are monoclonal antibodies targeting IGF-1/2; IGF-1R antagonists, which encompass some antibodies and kinase inhibitors; as well as insulin receptor substrate 1 (IRS-1) inhibitors, PI3K inhibitors, and mTOR inhibitors alone or in combination ( 25 , 52 , 64 , 65 ). These agents are of the same classes of drugs abandoned due to their high toxicity ( 41 , 53 ).…”