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Amplification of Crklinduces Transformation and Epidermal Published OnlineFirst October 17, 2011; DOI: 10.1158/2159-8290.CD-11-0046 research article Cheung et al. ReseaRch aRticle amplification of CRKL induces transformation and epidermal Growth Factor receptor inhibitor resistance in human Non–small cell lung cancers Hiu Wing Cheung1,6,9, Jinyan Du2,9, Jesse S. Boehm9, Frank He2,9, Barbara A. Weir1,9, Xiaoxing Wang1,6,9, Mohit Butaney1,3, Lecia V. Sequist5,6, Biao Luo9, Jeffrey A. Engelman5,6, David E. Root9, Matthew Meyerson1,4,6,7,9, Todd R. Golub2,4,6,9, Pasi A. Jänne1,3,6, and William C. Hahn1,4,6,8,9 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 immortal- ized 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 amplifica- tion in an EGFR inhibitor–treated lung adenocarcinoma that was not present before treatment. These observations demonstrate that CRKL overexpression induces cell transformation, creden- tial 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. Cancer Discovery; 1(7); 608–25. ©2011 AACR. 608 | CANCER DISCOVERY DECEMBER 2011 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 25, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst October 17, 2011; DOI: 10.1158/2159-8290.CD-11-0046 The BATTLE Trial: Personalizing Therapy for Lung Cancer research article intRoduction motif-containing proteins, such as Son of Sevenless (SOS), Although the prognosis for patients with non–small RAPGEF1 (also known as C3G) (22), p85 (23), ABL1, and cell lung cancer (NSCLC) who present with late-stage BCR-ABL (24, 25). Through these interactions, CRKL disease remains poor, somatic mutations of the epider- facilitates the timely and localized formation of pro- mal growth factor receptor (EGFR) serve as predictive tein complexes required for signal transduction in many biomarkers for both clinical response and survival in biological processes, including cell proliferation, survival, patients who receive EGFR inhibitors (1–7). Moreover, adhesion, and migration (20, 21). recent work indicates that mutations or translocations of CRKL and several proteins that interact with CRKL the ALK tyrosine kinase also occur in a subset of NSCLC have been implicated in cancer. Overexpression of CRKL (8, 9) and that tumors that harbor such mutations are in Rat-1 fibroblast cells has been shown to promote an- sensitive to ALK inhibitors (10, 11). Collectively, these chorage-independent growth, but the signaling pathways studies suggest that identifying and characterizing ge- necessary for this phenotype remain undefined (26, 27). netic alterations in NSCLC will provide new targets for Activating mutations of ALK have been shown to activate therapeutic strategies. RAP1 through CRKL-C3G complexes in neuroblastomas In previous work, researchers have identified 57 recur- (28). Moreover, expression of the oncogenic RET-PTC1 rent events of genomic gain or loss in primary NSCLC fusion protein leads to increased RAP1 activity, whereas N17 (12, 13). A small number of these recurrent genomic events expression of a dominant interfering RAP1 inhibits has been found to harbor known and novel oncogenes and proliferation of papillary thyroid carcinoma cells (29). tumor suppressor genes, including amplification or muta- However, it remains unclear how overexpression of CRKL tion in EGFR, KRAS, MYC, MDM2, TERT, CCND1, CCNE1, affects C3G-RAP1 signaling and whether RAP1 signaling and NKX2-1 and deletions of CDKN2A/B and PTEN (12, plays a role in proliferation, survival, and transformation 14–17). However, for many of these recurrently amplified of NSCLC cells. regions, the target gene(s) believed to drive the pathogen- In previous work, we and others demonstrated that esis of cancer remains to be identified and validated (12, a subset of NSCLC is dependent on CRKL expression for 14–17). For example, chromosome 22q11.21 is focally am- proliferation (17, 30). Moreover, overexpression of CRKL in plified in 3% of lung adenocarcinoma samples and the peak immortalized human lung epithelial cells promoted EGF- region contains 15 genes, including CRKL (v-crk sarcoma independent proliferation (17). Here we credential CRKL virus CT10 oncogene homolog (avian)-like) (12, 16, 17). as an oncogene in NSCLC that transforms human lung Recurrent amplifications of 22q11.21 have not been de- epithelial cells through coordinate activation of the RAS scribed in squamous cell lung carcinomas (18) or small cell and RAP1 pathways and is involved in resistance to EGFR lung carcinomas (19). inhibitors. CRKL is an adaptor protein that participates in signal transduction in response to both extracellular and intra- cellular stimuli, such as growth factors, cytokines, and the Results oncogenic BCR-ABL fusion protein (20, 21). CRKL consists amplification and Overexpression of the CRKL of an N-terminal Src homology 2 (SH2) domain followed Gene in Nsclc cells by two SH3 domains (SH2-SH3N-SH3C) (20). The SH2 In previous work, we and others found recurrent focal copy domain of CRKL binds to the phosphorylated Y-x-x-P number gain at chromosome 22q11.21 involving CRKL in 3% motif present in many docking proteins, such as BCAR1 of 371 primary lung adenocarcinomas, with another 13% of (also known as p130CAS), paxillin, and GAB (20, 21), tumors exhibiting broad copy number gain spanning that whereas the SH3N domain binds to proline-rich P-x-x-P-x-K region (12, 17). To identify other NSCLC cell lines that har- bor copy number gain of this region, we examined a panel of 84 NSCLC cell lines that had been characterized by high- Authors’ Affiliations: Departments of 1Medical Oncology and 2Pediatric density single-nucleotide polymorphism arrays (19, 31) and Oncology, 3Lowe Center for Thoracic Oncology, and 4Center for Cancer identified 6 cell lines with high-level focal amplifications of Genome Discovery, Dana-Farber Cancer Institute; 5Massachusetts General 22q11.21 (Fig. 1A). We confirmed that CRKL was amplified 6 7 Hospital Cancer Center; Harvard Medical School; Department of by FISH in 3 of these cell lines: HCC515, H1819, and H1755 Pathology, Harvard Medical School; 8Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston; and 9Broad Institute of (Fig. 1B). In contrast, in the HCC1833 cell line in which we Harvard and MIT, Cambridge, Massachusetts found normal 22q copy number (Fig. 1A), we detected only Note: Supplementary data for this article are available at Cancer 2 copies of the CRKL gene (Fig. 1B). To confirm these find- Discovery Online (http://www.cancerdiscovery.aacrjournals.org). ings, we also performed quantitative PCR to measure the Corresponding Author: William C. Hahn, Dana-Farber Cancer Institute, 450 copy number of CRKL and detected 12 to 18 copies of CRKL Brookline Avenue, Dana 1538, Boston, MA 02115. Phone: 617-632-2641; in NSCLC cell lines that harbored a 22q11.21 amplification Fax: 617-632-4005; E-mail: [email protected] (Fig. 1C). doi: 10.1158/2159-8290.CD-11-0046 To determine whether this observed gene amplification ©2011 American Association for Cancer Research. correlates with increased CRKL expression, we examined DECEMBER 2011 CANCER DISCOVERY | 609 Downloaded from cancerdiscovery.aacrjournals.org on September 25, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst October 17, 2011; DOI: 10.1158/2159-8290.CD-11-0046 research article Cheung et al. a c B D e Figure 1. Amplification and overexpression of the CRKL gene in NSCLC cell lines with amplification of 22q11.21. a, single-nucleotide polymorphism array colorgram showing genomic amplification of chromosome 22q11.21 in NSCLC cell lines. Regions of genomic amplification and deletion are denoted in red and blue, respectively. B, FISH of NSCLC cells with the use of a CRKL-specific probe (green, G) and a reference probe (red, R). HSR, homogenously staining region. c, quantitative PCR analysis of CRKL copy number in NSCLC cells. CRKL copy number in NSCLC cells was normalized to LINE-1 and immortalized AALE cells by use of the standard curve method. Data represent mean ± SD of triplicate measurements. D, quantitative RT-PCR analysis of CRKL mRNA levels in NSCLC cell lines and immortalized AALE cells. Data represent mean ± SD of triplicate measurements. e, immunoblot of CRKL in NSCLC cell lines and immortalized AALE cells. β-actin was used as a loading control. The relative intensity of CRKL levels is determined. expression data from the same panel of NSCLC cell lines
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