K-Ras4B/calmodulin/PI3Kα: A promising new adenocarcinoma-specific drug target?

Abstract

Introduction: Decades of efforts have yet to yield a safe and effective drug to target KRAS-driven pancreatic, colorectal and lung cancers; particularly those driven by the highly oncogenic splice variant KRAS4B. K-Ras4B's fairly smooth surface, cancer tissue/cell heterogeneity, tolerated lipid post-translational modification exchange, as well as drug-elicited toxicity present a daunting challenge.

Areas covered: Within this framework, hee we focus on a new adenocarcinoma-specific drug concept. Calmodulin (CaM) binds to K-Ras4B but not to the H-Ras or N-Ras isoforms. Physiologically, in calcium- and calmodulin-rich environments such as ductal tissues, calmodulin can sequester K-Ras4B from the membrane; in cancer, CaM/Ca(2+) can replace the missing receptor tyrosine kinase (RTK) signal, acting to fully activate PI3Kα.

Expert opinion: An oncogenic GTP-bound K-Ras4B/CaM/PI3Kα complex is supported by available experimental and clinical data; therefore, targeting it may address a pressing therapeutic need. High resolution electron microscopy (EM) or crystal structure of the tripartite complex would allow orthosteric or allosteric drug discovery to disrupt the CaM/PI3Kα interface and thus Akt/mTOR signaling. However, since drug resistance is expected to develop, combining it with compensatory pathways, particularly those involved in cell-cycle control, appears a reasonable strategy.

Keywords: K-Ras dimers; KRAS; KRAS4A; KRAS4B; allosteric drugs; calcium; calmodulin; colorectal cancer; lung cancer; orthosteric drugs; pancreatic cancer; pancreatic ductal adenocarcinomas (PDAC); small molecule drug.