title: Acquired resistance to dasatinib in lung cancer cell lines conferred by DDR2 gatekeeper mutation and NF1 loss.
abstract: The treatment of non-small cell lung cancer has evolved dramatically over the past decade with the adoption of widespread use of effective targeted therapies in patients with distinct molecular alterations. In lung squamous cell carcinoma (lung SqCC), recent studies have suggested that DDR2 mutations are a biomarker for therapeutic response to dasatinib and clinical trials are underway testing this hypothesis. Although targeted therapeutics are typically quite effective as initial therapy for patients with lung cancer, nearly all patients develop resistance with long-term exposure to targeted drugs. Here, we use DDR2-dependent lung cancer cell lines to model acquired resistance to dasatinib therapy. We perform targeted exome sequencing to identify two distinct mechanisms of acquired resistance: acquisition of the T654I gatekeeper mutation in DDR2 and loss of NF1. We show that NF1 loss activates a bypass pathway, which confers ERK dependency downstream of RAS activation. These results indicate that acquired resistance to dasatinib can occur via both second-site mutations in DDR2 and by activation of bypass pathways. These data may help to anticipate mechanisms of resistance that may be identified in upcoming clinical trials of anti-DDR2 therapy in lung cancer and suggest strategies to overcome resistance.
authors.affiliation: Corresponding Author: Peter S. Hammerman, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana 810A, Boston, MA 02215. phammerman@partners.org.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Beauchamp
authors.forename: Brittany A
authors.initials: BA
authors.lastname: Woods
authors.forename: Austin M
authors.initials: AM
authors.lastname: Dulak
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Xu
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
authors.forename: Kwok-kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004252:DNA Mutational Analysis; D000069439:Dasatinib; D000070818:Discoidin Domain Receptors; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D059472:Exome / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D025542:Neurofibromin 1 / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011975:Receptors, Mitogen / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D025542:Neurofibromin 1; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011975:Receptors, Mitogen; D013844:Thiazoles; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; D000069439:Dasatinib