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Int J Cancer. 2013 Jan 15;132(2):E74-84. doi: 10.1002/ijc.27813. Epub 2012 Oct 3.

Overcoming erlotinib resistance with tailored treatment regimen in patient-derived xenografts from naïve Asian NSCLC patients.

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1
Crown Bioscience, Inc, 3375 Scott Blvd, suite 108, Santa Clara, CA 95054, USA.

Abstract

Overall benefits of EGFR-TKIs are limited because these treatments are largely only for adenocarcinoma (ADC) with EGFR activating mutation. The treatments also usually lead to development of resistances. We have established a panel of patient-derived xenografts (PDXs) from treatment naïve Asian NSCLC patients, including those containing "classic" EGFR activating mutations. Some of these EGFR-mutated PDXs do not respond to erlotinib: LU1868 containing L858R/T790M mutations, and LU0858 having L858R mutation as well as c-MET gene amplification, both squamous cell carcinoma (SCC). Treatment of LU0858 with crizotinib, a small molecule inhibitor for ALK and c-MET, inhibited tumor growth and c-MET activity. Combination of erlotinib and crizotinib caused complete response, indicating the activation of both EGFR and c-MET promote its growth/survival. LU2503 and LU1901, both with wild-type EGFR and c-MET gene amplification, showed complete response to crizotinib alone, suggesting that c-MET gene amplification, not EGFR signaling, is the main oncogenic driver. Interestingly, LU1868 with the EGFR L858R/T790M, but without c-met amplification, had a complete response to cetuximab. Our data offer novel practical approaches to overcome the two most common resistances to EGFR-TKIs seen in the clinic using marketed target therapies.

PMID:
22948846
DOI:
10.1002/ijc.27813
[Indexed for MEDLINE]
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