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The key role of calmodulin in kras-driven adenocarcinomas

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Nussinov, Ruth
Tsai, Chung-Jung
Jang, Hyunbum

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KRAS4B is a highly oncogenic splice variant of the KRAS isoform. It is the only isoform associated with initiation of adenocarcinomas. Insight into why and how KRAS4B can mediate ductal adenocarcinomas, particularly of the pancreas, is vastly important for its therapeutics. Here we point out the overlooked critical role of calmodulin (CaM). Calmodulin selectively binds to GTP-bound K-Ras4B; but not to other Ras isoforms. Cell proliferation and growth require the MAPK (Raf/MEK/ERK) and PI3K/Akt pathways. We propose that Ca2+/calmodulin promote PI3K alpha/Akt signaling, and suggest how. The elevated calcium levels clinically observed in adenocarcinomas may explain calmodulin's involvement in recruiting and stimulating PI3K alpha through interaction with its n/cSH2 domains as well as K-Ras4B; importantly, it also explains why K-Ras4B specifically is a key player in ductal carcinomas, such as pancreatic (PDAC), colorectal (CRC), and lung cancers. We hypothesize that calmodulin recruits and helps activate PI3K alpha at the membrane, and that this is the likely reason for Ca2+/calmodulin dependence in adenocarcinomas. Calmodulin can contribute to initiation/progression of ductal cancers via both PI3K alpha/Akt and Raf/MEK/ERK pathways. Blocking the K-Ras4B/MAPK pathway and calmodulin/PI3Ka binding in a K-Ras4B/calmodulin/PI3K alpha trimer could be a promising adenocarcinoma-specific therapeutic strategy.

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Amer Assoc Cancer Research

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Oncology, Cell biology

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Molecular Cancer Research

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10.1158/1541-7786.MCR-15-0165

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