Genomic Complexity and AKT Dependence in Serous Ovarian Cancer

Abstract

Effective oncoprotein-targeted therapies have not yet been developed for ovarian cancer. To explore the role of PI3 kinase/AKT signaling in this disease, we performed a genetic and functional analysis of ovarian cancer cell lines and tumors. PI3K pathway alterations were common in both, but the spectrum of mutational changes differed. Genetic activation of the pathway was necessary, but not sufficient, to confer sensitivity to selective inhibition of AKT and cells with RAS pathway alterations or RB1 loss were resistant to AKT inhibition, whether or not they had coexistent PI3K/AKT pathway activation. Inhibition of AKT1 caused growth arrest in a subset of ovarian cell lines, but not in those with AKT3 expression, which required pan-AKT inhibition. Thus, a subset of ovarian tumors are sensitive to AKT inhibition, but the genetic heterogeneity of the disease suggests that effective treatment with AKT pathway inhibitors will require a detailed molecular analysis of each patient’s tumor.

In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene

“…Several studies have addressed PI3K/AKT pathway inhibition in ovarian cancer. In one study, a subset of ovarian cancer cell lines was sensitive to inhibition of AKT1 and AKT2, whereas those expressing AKT3 required inhibition of all three isoforms (28). In a separate study, modest clinical responses were seen in a phase-I trial incorporating mTOR inhibitors in the patients with PIK3CA mutant compared with PIK3CA wild-type cancers (36).…”

“…Hanrahan et al (28) recently reported a substantial number of PI3K pathway alterations in ovarian cancer. We extended this analysis by analyzing a substantially larger number the number of samples and also incorporating GAB2 in our analysis.…”

“…Having shown that the PI3K pathway was required for GAB2-mediated transformation and that activated AKT1 could partially rescue GAB2-dependent cell lines depleted of GAB2, we next determined whether GAB2 alterations represented a feature that correlated with enhanced sensitivity to PI3K pathway inhibition. Several studies suggest that PI3K inhibition attenuated GAB2-dependent migration phenotypes (24,26) and pointed to the types of pathway alterations that activate AKT1 (28). However, although recent work has been directed at correlating PI3K pathway alterations with sensitivity to pathway inhibition in breast cancer (29), it is unclear whether increased GAB2 expression increases cell sensitivity to PI3K pathway inhibition in a manner similar to the sensitivity conferred by canonical mutations in PIK3CA and PTEN.…”

ABT‑737 and pictilisib synergistically enhance pitavastatin‑induced apoptosis in ovarian cancer cells

“…Dual inhibition of PI3K/Akt/mTOR signalling with a combination of pictilisib and pitavastatin increased apoptosis in Ovcar-3 cells, whilst demonstrating antagonism in A2780 and Igrov-1 cells. Ovcar-3, Ovcar-8, Igrov-1 and A2780 cells have PI3K/Akt pathway alterations consistent with activation of PI3K/Akt signalling, suggesting that these cell lines may be particularly sensitive to PI3K pathway inhibition (23,24). This was supported by the submicromolar IC 50 values obtained for pictilisib in all cell lines tested.…”

“…This was supported by the submicromolar IC 50 values obtained for pictilisib in all cell lines tested. The lack of synergy between pitavastatin and pictisilib in A2780 and Igrov-1 cells may be due to PTEN deletions in these cell lines, resulting in low or undetectable levels of PTEN protein (23). This may hyperactivate the Akt The number of dead Ovcar-3 and Igrov-1 cells was determined by trypan blue staining following exposure for 72 h to either solvent (DMSO), or 12 and 6 µM pitavastatin, and 1 and 0.6 µM ABT-737, 2 and 3 µM obatoclax, or 2 and 0.7 µM pictilisib.…”