title: LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition.
abstract: LKB1/STK11 is a multitasking tumour suppressor kinase. Germline inactivating mutations of the gene are responsible for the Peutz-Jeghers hereditary cancer syndrome. It is also somatically inactivated in approximately 30% of non-small-cell lung cancer (NSCLC). Here, we report that LKB1/KRAS mutant NSCLC cell lines are sensitive to the MEK inhibitor CI-1040 shown by a dose-dependent reduction in proliferation rate, whereas LKB1 and KRAS mutations alone do not confer similar sensitivity. We show that this subset of NSCLC is also sensitised to the mTOR inhibitor rapamycin. Importantly, the data suggest that LKB1/KRAS mutant NSCLCs are a genetically and functionally distinct subset and further suggest that this subset of lung cancers might afford an opportunity for exploitation of anti-MAPK/mTOR-targeted therapies.
authors.affiliation: Cancer Genome Project, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: C L
authors.initials: CL
authors.lastname: Mahoney
authors.forename: B
authors.initials: B
authors.lastname: Choudhury
authors.forename: H
authors.initials: H
authors.lastname: Davies
authors.forename: S
authors.initials: S
authors.lastname: Edkins
authors.forename: C
authors.initials: C
authors.lastname: Greenman
authors.forename: G van
authors.initials: Gv
authors.lastname: Haaften
authors.forename: T
authors.initials: T
authors.lastname: Mironenko
authors.forename: T
authors.initials: T
authors.lastname: Santarius
authors.forename: C
authors.initials: C
authors.lastname: Stevens
authors.forename: M R
authors.initials: MR
authors.lastname: Stratton
authors.forename: P A
authors.initials: PA
authors.lastname: Futreal
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D000903:Antibiotics, Antineoplastic; D001549:Benzamides; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D058570:TOR Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000091162:AMP-Activated Protein Kinase Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D020123:Sirolimus