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

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KU Authors

Co-Authors

Nussinov, Ruth
Tsai, Chung-Jung
Jang, Hyunbum

Advisor

Publication Date

2016

Language

English

Type

Review

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Volume Title

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 PI3K alpha. Expert opinion: An oncogenic GTP-bound K-Ras4B/CaM/PI3K alpha 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/PI3K alpha 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.

Description

Source:

Expert Opinion on Therapeutic Targets

Publisher:

Taylor and Francis Ltd

Keywords:

Subject

Pharmacology, Pharmacy

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