Amplification of CRKL induces transformation and epidermal growth factor receptor inhibitor resistance in human non-small cell lung cancers.
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Abstract | UNLABELLED: 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. |
Year of Publication | 2011
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Journal | Cancer Discov
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Volume | 1
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Issue | 7
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Pages | 608-25
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Date Published | 2011 Dec
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ISSN | 2159-8290
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URL | |
DOI | 10.1158/2159-8290.CD-11-0046
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PubMed ID | 22586683
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PubMed Central ID | PMC3353720
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Grant list | RC2 CA148268-02 / CA / NCI NIH HHS / United States
R33 CA128625 / CA / NCI NIH HHS / United States
R01 CA109038 / CA / NCI NIH HHS / United States
R33 CA128625-01A1 / CA / NCI NIH HHS / United States
R01 CA109038-05A1 / CA / NCI NIH HHS / United States
Howard Hughes Medical Institute / United States
R33 CA128625-02 / CA / NCI NIH HHS / United States
U54 CA112962-08 / CA / NCI NIH HHS / United States
P50 CA090578 / CA / NCI NIH HHS / United States
R33 CA128625-03 / CA / NCI NIH HHS / United States
R01 CA135257 / CA / NCI NIH HHS / United States
RC2 CA148268-01 / CA / NCI NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States
RC2 CA148268 / CA / NCI NIH HHS / United States
R01 CA114465 / CA / NCI NIH HHS / United States
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