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

Ruth Nussinov*, Serena Muratcioglu, Chung Jung Tsai, Hyunbum Jang, Attila Gursoy, Ozlem Keskin

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

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/Ca2+ 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.

Original languageEnglish
Pages (from-to)831-842
Number of pages12
JournalExpert Opinion on Therapeutic Targets
Volume20
Issue number7
DOIs
StatePublished - 2 Jul 2016

Funding

FundersFunder number
National Cancer InstituteZIABC010441

    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

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