@article{a220675cd04d454983ff372a9d437e4d,
title = "K-Ras4B/calmodulin/PI3Kα: A promising new adenocarcinoma-specific drug target?",
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{\textquoteright}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.",
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",
author = "Ruth Nussinov and Serena Muratcioglu and Tsai, {Chung Jung} and Hyunbum Jang and Attila Gursoy and Ozlem Keskin",
note = "Publisher Copyright: {\textcopyright} 2016 Informa UK Limited, trading as Taylor & Francis Group.",
year = "2016",
month = jul,
day = "2",
doi = "10.1517/14728222.2016.1135131",
language = "אנגלית",
volume = "20",
pages = "831--842",
journal = "Expert Opinion on Therapeutic Targets",
issn = "1472-8222",
publisher = "Taylor and Francis Ltd.",
number = "7",
}