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Cancer Discov DOI:10.1158/2159-8290.CD-11-0046

Amplification of CRKL induces transformation and epidermal growth factor receptor inhibitor resistance in human non-small cell lung cancers.

Publication TypeJournal Article
Year of Publication2011
AuthorsCheung, HWing, Du, J, Boehm, JS, He, F, Weir, BA, Wang, X, Butaney, M, Sequist, LV, Luo, B, Engelman, JA, Root, DE, Meyerson, M, Golub, TR, Jänne, PA, Hahn, WC
JournalCancer Discov
Volume1
Issue7
Pages608-25
Date Published2011 Dec
ISSN2159-8290
KeywordsAdaptor Proteins, Signal Transducing, Adenocarcinoma, Cell Death, Cell Line, Tumor, Cell Transformation, Neoplastic, Chromosomes, Human, Pair 22, Epithelial Cells, Extracellular Signal-Regulated MAP Kinases, Gene Amplification, Humans, Lung Neoplasms, Mutation, Neurofibromin 1, Nuclear Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins p21(ras), Quinazolines, raf Kinases, Receptor, Epidermal Growth Factor, Signal Transduction, SOS1 Protein, Telomere-Binding Proteins
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.

URLhttp://cancerdiscovery.aacrjournals.org/cgi/pmidlookup?view=long&pmid=22586683
DOI10.1158/2159-8290.CD-11-0046
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22586683?dopt=Abstract

Alternate JournalCancer Discov
PubMed ID22586683
PubMed Central IDPMC3353720
Grant ListRC2 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