title: Activation of RAS family members confers resistance to ROS1 targeting drugs.
abstract: The ROS1 tyrosine kinase is activated in lung cancer as a consequence of chromosomal rearrangement. Although high response rates and disease control have been observed in lung cancer patients bearing rearranged ROS1 tumors (ROS1+) treated with the kinase inhibitor crizotinib, many of these patients eventually relapse.To identify mechanisms of resistance to ROS1 inhibitors we generated resistant cells from HCC78 lung cancer cells bearing the SLC34A2-ROS1 rearrangement. We found that activation of the RAS pathway in the HCC78 cell model, due to either KRAS/NRAS mutations or to KRAS amplification, rendered the cells resistant to ROS1 inhibition. These cells were cross-resistant to different ROS1 inhibitors, but sensitive to inhibitors of the RAS signaling pathway. Interestingly, we identified focal KRAS amplification in a biopsy of a tumor from a patient that had become resistant to crizotinib treatment.Altogether our data suggest that the activation of members of the RAS family can confer resistance to ROS1 inhibitors. This has important clinical implications as: (i) RAS genetic alterations in ROS1+ primary tumors are likely negative predictors of efficacy for targeted drugs and (ii) this kind of resistance is unlikely to be overcome by the use of more specific or more potent ROS1 targeting drugs.
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Torino, Italy.
authors.forename: Marilisa
authors.initials: M
authors.lastname: Cargnelutti
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Torino, Italy.|Department of Oncology, University of Torino, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Corso
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Torino, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Pergolizzi
authors.affiliation: Janssen Research & Development, Janssen-Cilag, Val-de-Reuil, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Mévellec
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Dara L
authors.initials: DL
authors.lastname: Aisner
authors.affiliation: Medical University of Gdansk, Poland.
authors.forename: Rafal
authors.initials: R
authors.lastname: Dziadziuszko
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.|Department of Medicine, Division of Medical Oncology University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Torino, Italy.|Department of Oncology, University of Torino, Italy.
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.affiliation: Department of Medicine, Division of Medical Oncology University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Doebele
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Jorge
authors.initials: J
authors.lastname: Vialard
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Torino, Italy.|Department of Oncology, University of Torino, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Giordano
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015321:Gene Rearrangement; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; C493557:SLC34A2 protein, human; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; D000077547:Crizotinib; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: RAS; ROS1; drug resistance; lung cancer; targeted therapy