title: K-Ras4B/calmodulin/PI3Kα: A promising new adenocarcinoma-specific drug target?
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , National Cancer Institute at Frederick , Frederick , MD , USA.|b Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine , Tel Aviv University , Tel Aviv , Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.affiliation: c Department of Chemical and Biological Engineering , Koc University , Istanbul , Turkey.
authors.forename: Serena
authors.initials: S
authors.lastname: Muratcioglu
authors.affiliation: a Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , National Cancer Institute at Frederick , Frederick , MD , USA.
authors.forename: Chung-Jung
authors.initials: CJ
authors.lastname: Tsai
authors.affiliation: a Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , National Cancer Institute at Frederick , Frederick , MD , USA.
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
authors.affiliation: d Department of Computer Engineering , Koc University , Istanbul , Turkey.
authors.forename: Attila
authors.initials: A
authors.lastname: Gursoy
authors.affiliation: c Department of Chemical and Biological Engineering , Koc University , Istanbul , Turkey.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Keskin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002147:Calmodulin / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002147:Calmodulin; C117307:KRAS protein, human; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D016283:Proto-Oncogene Proteins p21(ras)
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