title: A combinatorial strategy for treating KRAS-mutant lung cancer.
abstract: Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards identifying combination targets for trametinib, a MEK inhibitor approved by the US Food and Drug Administration, which acts downstream of KRAS to suppress signalling through the mitogen-activated protein kinase (MAPK) cascade. Informed by a short-hairpin RNA screen, we show that trametinib provokes a compensatory response involving the fibroblast growth factor receptor 1 (FGFR1) that leads to signalling rebound and adaptive drug resistance. As a consequence, genetic or pharmacological inhibition of FGFR1 in combination with trametinib enhances tumour cell death in vitro and in vivo. This compensatory response shows distinct specificities: it is dominated by FGFR1 in KRAS-mutant lung and pancreatic cancer cells, but is not activated or involves other mechanisms in KRAS wild-type lung and KRAS-mutant colon cancer cells. Importantly, KRAS-mutant lung cancer cells and patients’ tumours treated with trametinib show an increase in FRS2 phosphorylation, a biomarker of FGFR activation; this increase is abolished by FGFR1 inhibition and correlates with sensitivity to trametinib and FGFR inhibitor combinations. These results demonstrate that FGFR1 can mediate adaptive resistance to trametinib and validate a combinatorial approach for treating KRAS-mutant lung cancer.
authors.forename: Eusebio
authors.initials: E
authors.lastname: Manchado
authors.forename: Susann
authors.initials: S
authors.lastname: Weissmueller
authors.forename: John P
authors.initials: JP
authors.lastname: Morris
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chen
authors.forename: Ramona
authors.initials: R
authors.lastname: Wullenkord
authors.forename: Amaia
authors.initials: A
authors.lastname: Lujambio
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.forename: John T
authors.initials: JT
authors.lastname: Poirier
authors.forename: Justin F
authors.initials: JF
authors.lastname: Gainor
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Corcoran
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D050505:Mutant Proteins / Q000235:genetics; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use*; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D007093:Imidazoles; C117307:KRAS protein, human; D050505:Mutant Proteins; D011724:Pyridazines; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C545373:ponatinib; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020929:Mitogen-Activated Protein Kinase Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)