Abstract
We previously identified a region of recurrent amplification on chromosome 22q11.21 in a subset of primary lung adenocarcinomas. Here we show that CRKL, encoding for an adaptor protein, is amplified and overexpressed in non-small cell lung cancer (NSCLC) cells that harbor 22q11.21 amplifications. Overexpression of CRKL in immortalized human airway epithelial cells promoted anchorage-independent growth and tumorigenicity. Oncogenic CRKL activates the SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL in NSCLC cells that harbor CRKL amplifications induced cell death. Overexpression of CRKL in epidermal growth factor receptor (EGFR)-mutant cells induces resistance to gefitinib by activating extracellular signal-regulated kinase and AKT signaling. We identified CRKL amplification in an EGFR inhibitor-treated lung adenocarcinoma that was not present before treatment. These observations demonstrate that CRKL overexpression induces cell transformation, credential CRKL as a therapeutic target for a subset of NSCLC that harbor CRKL amplifications, and implicate CRKL as an additional mechanism of resistance to EGFR-directed therapy.
Significance:
These studies credential CRKL as an oncogene in a subset of NSCLC. Overexpression of CRKL induces cell transformation and resistance to epidermal growth factor receptor inhibitor treatment and suggest that therapeutic interventions targeting CRKL may confer a clinical benefit in a defined subset of NSCLCs.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Adenocarcinoma / genetics*
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Adenocarcinoma / therapy*
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Adenocarcinoma of Lung
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Cell Death / genetics
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Chromosomes, Human, Pair 22
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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ErbB Receptors / antagonists & inhibitors*
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gefitinib
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Gene Amplification
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Humans
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Lung Neoplasms / genetics*
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Lung Neoplasms / therapy*
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Mutation
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Neurofibromin 1 / genetics
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Neurofibromin 1 / metabolism
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins p21(ras) / genetics
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Proto-Oncogene Proteins p21(ras) / metabolism
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Quinazolines / pharmacology
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SOS1 Protein / genetics
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SOS1 Protein / metabolism
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Shelterin Complex
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Signal Transduction
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Telomere-Binding Proteins / genetics
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Telomere-Binding Proteins / metabolism
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raf Kinases / genetics
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raf Kinases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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CRKL protein
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Neurofibromin 1
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Nuclear Proteins
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Quinazolines
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SOS1 Protein
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Shelterin Complex
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TERF2IP protein, human
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Telomere-Binding Proteins
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EGFR protein, human
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ErbB Receptors
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Proto-Oncogene Proteins c-akt
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raf Kinases
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Extracellular Signal-Regulated MAP Kinases
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Proto-Oncogene Proteins p21(ras)
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Gefitinib