title: BAY61-3606 affects the viability of colon cancer cells in a genotype-directed manner.
abstract: BACKGROUND
  K-RAS mutation poses a particularly difficult problem for cancer therapy. Activating mutations in K-RAS are common in cancers of the lung, pancreas, and colon and are associated with poor response to therapy. As such, targeted therapies that abrogate K-RAS-induced oncogenicity would be of tremendous value.
  
  
  METHODS
  We searched for small molecule kinase inhibitors that preferentially affect the growth of colorectal cancer cells expressing mutant K-RAS. The mechanism of action of one inhibitor was explored using chemical and genetic approaches.
  
  
  RESULTS
  We identified BAY61-3606 as an inhibitor of proliferation in colorectal cancer cells expressing mutant forms of K-RAS, but not in isogenic cells expressing wild-type K-RAS. In addition to its anti-proliferative effects in mutant cells, BAY61-3606 exhibited a distinct biological property in wild-type cells in that it conferred sensitivity to inhibition of RAF. In this context, BAY61-3606 acted by inhibiting MAP4K2 (GCK), which normally activates NFκβ signaling in wild-type cells in response to inhibition of RAF. As a result of MAP4K2 inhibition, wild-type cells became sensitive to AZ-628, a RAF inhibitor, when also treated with BAY61-3606.
  
  
  CONCLUSIONS
  These studies indicate that BAY61-3606 exerts distinct biological activities in different genetic contexts.
authors: Molecular Pathology Unit, Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors: Ken S
authors: KS
authors: Lau
authors: Tinghu
authors: T
authors: Zhang
authors: Krystle R
authors: KR
authors: Kendall
authors: Douglas
authors: D
authors: Lauffenburger
authors: Nathanael S
authors: NS
authors: Gray
authors: Kevin M
authors: KM
authors: Haigis
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D020134:Catalytic Domain; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D011905:Genes, ras; D005838:Genotype; D000081410:Germinal Center Kinases; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D048490:raf Kinases / Q000037:antagonists & inhibitors
chemical_list: C477642:2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide; D000970:Antineoplastic Agents; D000081410:Germinal Center Kinases; D011743:Pyrimidines; D009536:Niacinamide; D017346:Protein Serine-Threonine Kinases; D048490:raf Kinases