title: KRAS-Mutant Lung Cancers in the Era of Targeted Therapy.
abstract: KRAS-mutant lung cancers account for approximately 25% of non-small cell lung carcinomas, thus representing an enormous burden of cancer worldwide. KRAS mutations are clear drivers of tumor growth and are characterized by a complex biology involving the interaction between mutant KRAS, various growth factor pathways, and tumor suppressor genes. While KRAS mutations are classically associated with a significant smoking history, they are also identified in a substantial proportion of never-smokers. These mutations are found largely in lung adenocarcinomas with solid growth patterns and tumor-infiltrating lymphocytes. A variety of tools are available for diagnosis including Sanger sequencing, multiplex mutational hotspot profiling, and next-generation sequencing. The prognostic and predictive roles of KRAS status remain controversial. It has become increasingly clear, however, that KRAS mutations drive primary resistance to EGFR tyrosine kinase inhibition. Until recently, mutant KRAS was not thought of as a clinically-targetable driver in lung cancers. With the expansion of our knowledge regarding the biology of KRAS-mutant lung cancers and the role of MEK and PI3K/mTOR inhibition, the face of targeted therapeutics for this genomic subset of patients is slowly beginning to change.
authors.affiliation: Department of Medicine, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Jarushka
authors.initials: J
authors.lastname: Naidoo
authors.affiliation: Department of Medicine, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. drilona@mskcc.org.
authors.forename: Alexander
authors.initials: A
authors.lastname: Drilon
mesh_terms: D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D058990:Molecular Targeted Therapy; D009154:Mutation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000502:physiology; D048490:raf Kinases / Q000037:antagonists & inhibitors
chemical_list: D006360:Heat-Shock Proteins; C117307:KRAS protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051231:Farnesyltranstransferase; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D048490:raf Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Erlotinib resistance; Hsp90 inhibition; KRAS mutation; Lung adenocarcinoma; Lung cancer; MEK inhibition; PI3K inhibition; Selumetinib; Targeted therapy; mTOR inhibition