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.Colorectal cancer (CRC) is a commonly diagnosed malignancy with over one million cases worldwide.

Current treatment strategies for inhibiting mTOR in cancer

“…Mutational activation of KRAS, when accompanied by a PIK3CA activating mutation, resulted in resistance to BEZ235 in colorectal carcinoma cells [80]. In T cell acute lymphoblastic leukemia cell lines, PI-103 caused upregulation of Notch1/c-Myc signaling, which led to an impaired cytotoxic response [81].…”

mTOR in health and in sickness

“…Activating mutations in the KRAS gene result in resistance to treatment of colorectal cancer cell lines with BEZ235, a PI3K/mTOR inhibitor [133]. Furthermore, amplification of eIF4E or c-MYC confers resistance to treatment with the same inhibitor in tumor cell lines [134].…”

What is the future potential of the PI3K pathway in colorectal cancer treatment?

“…Preclinical models have indicated intrinsic resistance associated with simultaneous mutation of KRAS or BRAF in PIK3CA-mutated tumors, highlighting the need for combination strategies [16,17]. Similarly, the exonic location of PIK3CA mutations may influence response to PI3K pathway inhibition; for example, a recent analysis of multiple CRC cohorts suggested that mutations in PIK3CA exon 20, but not exon 9, are predictive of resistance to EGFR inhibition [18].…”

“…Direct testing for PIK3CA mutation and PTEN expression in isolation may have limited predictive utility, with frequent co-occurrence of resistance KRAS or BRAF mutations [17]. Molecular predictive signatures, rather than individual biomarkers, may therefore be required, potentially comprising mutation, gene and protein expression.…”