Dual Targeting of mTOR Activity with Torin2 Potentiates Anticancer Effects of Cisplatin in Epithelial Ovarian Cancer

Abstract

Mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K) are two key components of PI3K/Akt/mTOR signaling pathway. Dysregulation of these pathways have been found in many cancers, including epithelial ovarian cancer (EOC), however, the role of mTOR has not been fully elucidated in Middle Eastern EOC. Therefore, we investigated the activation of mTOR complexes (mTORC1 and mTORC2) in a cohort of 156 EOC from Saudi Arabia by immunohistochemistry in a tissue microarray format. mTORC1 and mTORC2 were found to be activated in 55 of 146 (37.7%) and 63 of 140 (45%) of EOC samples, respectively. mTORC1 was significantly associated with mTORC2 (p < 0.0001) activation and both mTOR complexes were significantly associated with p-AKT (p = 0.0205 and 0.0298) and p-P70S6 (p < 0.0001 and 0.0035), respectively. Interestingly, mTOR activation incurred a poor progression-free survival (PFS) (p = 0.0188) in EOC. Next, the in vitro effect of inactivation of mTOR complexes was evaluated using a second-generation mTOR inhibitor, Torin2, on a panel of EOC cell lines. Torin2 treatment decreased cell viability and induced apoptosis in a dose-dependent manner via inactivation of mTORC1 and mTORC2 and their downstream targets in EOC cell lines. Furthermore, treatment of EOC cells with a subtoxic dose of Torin2 potentiated a cisplatin-induced apoptotic response in EOC cell lines. Finally, we studied the in vivo effect of a combination of Torin2 and cisplatin and found that this combination synergistically inhibited tumor growth in nude mice. These studies highlight the importance of targeting the mTOR survival pathway and suggest that cotreatment with cisplatin and Torin2 may be beneficial for the management of EOC.

PI3K/AKT/mTOR Pathway in Ovarian Cancer Treatment: Are We on the Right Track?

“…Another study conducted by Hussein et al, where a second-generation mTor inhibitor, Torin2 was tested, resulted in the inhibition of tumor cell viability and induction of apoptosis in epithelial ovarian cancer. In addition, this study found that combination in vivo of Torin2 and cisplatin synergistically inhibited tumor growth in nude mice, confirming the hypothesis that mTor inhibitors might serve as single agent therapies as well as in combination with other treatment options, acting either as synergic agents or sensitizing ones 61 , 64 . In this scenario, it was also recently shown that the combination of PIK3 inhibitor BKM120 with PARP inhibitor olaparib resulted in reduced proliferation, survival and invasion in different ovarian cancer cell lines harboring PIK3CA mutations and in a significantly decreased BRCA1 expression in SKOV3 ovarian cancer cells 65 .…”

Torin2 Suppresses Ionizing Radiation-Induced DNA Damage Repair

“…This decision allowed us to distinguish effects related to DNA repair from autophagic responses (19). Moreover, a recently reported study demonstrated that at sublethal doses, Torin2 synergizes with cisplatin to inhibit the growth of ovarian carcinoma cell lines (69), suggesting that low doses of Torin2 are capable of enhancing the DNA damage response when combined with existing radiotherapeutic agents routinely used in clinical settings. Importantly, Torin2 was also reported to have a good safety profile in mouse models, suggesting that the drug may not have deleterious effects on normal tissues (16).…”

Cisplatin based therapy: the role of the mitogen activated protein kinase signaling pathway

“…In vivo studies also revealed that in combination of Torin2 and cisplatin, tumor growth in nude mice was synergistically inhibited. Overall, such studies highlight the importance and potential of targeting the mTOR survival pathway, suggesting that co-treatment of cisplatin and mTOR inhibitors, such as Torin2, may be beneficial for the management of EOC and various other resistant cancers [ 64 ].…”