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.

• Authors: Areumnuri Kim, Jung-Eun Lee, Seung-Sook Lee, Cherin Kim, Sun-Joo Lee, Won-Suk Jang, Sunhoo Park
• Journal: International journal of cancer (Int J Cancer) Vol. 133 Issue 4 Pg. 984-96 (Aug 15 2013) ISSN: 1097-0215 [Electronic] United States
• PMID: 23475782 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 UICC.

Chemical References

• Antineoplastic Agents
• Imidazoles
• Phosphoinositide-3 Kinase Inhibitors
• Quinolines
• MTOR protein, human
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• TOR Serine-Threonine Kinases
• dactolisib

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Cell Line, Tumor
• Class I Phosphatidylinositol 3-Kinases
• Colorectal Neoplasms (enzymology, metabolism, pathology)
• Female
• Flow Cytometry
• Genes, ras
• Humans
• Imidazoles (pharmacology)
• Immunohistochemistry
• Mice
• Mice, Inbred BALB C
• Mutation
• Phosphatidylinositol 3-Kinases (genetics)
• Phosphoinositide-3 Kinase Inhibitors
• Quinolines (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Xenograft Model Antitumor Assays