Coexistent mutations of KRAS and PIK3CA affect the efficacy of NVP-BEZ235, a dual PI3K/MTOR inhibitor, in regulating the PI3K/MTOR pathway in colorectal cancer

Abstract

Colorectal cancer (CRC) with mutational activation of KRAS is observed frequently. In addition, PIK3CA mutations commonly coexist with KRAS mutations and lead to additive activation of the PI3K/MTOR signaling pathway. Here, we investigated how CRC cells that harbor KRAS and PIK3CA mutations affect sensitivity to inhibition of PI3K/MTOR with NVP-BEZ235 (BEZ235). We selected CRC patient samples and assessed their mutational status. CRC patients with KRAS or PIK3CA mutations show activation of AKT and MTOR, particularly when KRAS and PIK3CA mutations coexist. Suppression of PI3K/MTOR by BEZ235 results in a growth inhibitory effect and enhanced apoptosis via BIM activation in KRAS mutant cells. Mutational activation of KRAS when accompanied by a PIK3CA mutation converges at PI3K/MTOR pathway activation, resulting in resistance to BEZ235. BIM knockdown blocked the apoptotic response to BEZ235 in KRAS mutant cells, suggesting that PI3K inhibition leads to BIM accumulation. Moreover, BEZ235 treatment resulted in induction of FOXO3A activity and its induced transcription of BIM activation, which sensitized cells to cytotoxic agents leading to apoptosis in double mutant cells in vitro and in vivo. Taken together, our data suggest that targeting PI3K/MTOR sensitizes cells to apoptosis, implying that activation of PI3K/MTOR signaling via KRAS or PIK3CA mutation is an important pathway in CRC cell growth. Based on these results, coexistent KRAS and PIK3CA mutations confer resistance to BEZ235 via suppression of BIM-induced apoptosis, suggesting that combined treatment with conventional chemoagents is a potential strategy in the clinic. What's new? Two of the mutations frequently seen in colorectal cancer are KRAS and PI3KCA, which boost the PI3K/AKT/MTOR signal transduction pathways that stimulate cell proliferation and inhibit apoptosis. Patients with both these mutations tend to have poor prognosis. In this study, the authors investigated how mutations in KRAS or PI3KCA affect sensitivity to a new antiproliferative agent, BEZ235. BEZ235 inhibits PI3K and MTOR, sensitizing the cell to apoptosis. The authors looked at KRAS mutant cell lines with or without mutations in PI3KCA to see how well BEZ235 could halt their growth. Dual mutations in these two genes, which step up the activity of the PI3K/MTOR signaling pathway, do allow the cell to sidestep the effects of BEZ235, they found. Copyright © 2013 UICC.