Publication: K-Ras4B/calmodulin/PI3Kα: a promising new adenocarcinoma-specific drug target?
Program
KU Authors
Co-Authors
Nussinov, Ruth
Tsai, Chung-Jung
Jang, Hyunbum
Advisor
Publication Date
2016
Language
English
Type
Review
Journal Title
Journal ISSN
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