title: Overcoming erlotinib resistance with tailored treatment regimen in patient-derived xenografts from naïve Asian NSCLC patients.
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.
authors.affiliation: Crown Bioscience, Inc, 3375 Scott Blvd, suite 108, Santa Clara, CA 95054, USA.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Yang
authors.forename: Baoen
authors.initials: B
authors.lastname: Shan
authors.forename: Qiaoxia
authors.initials: Q
authors.lastname: Li
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Song
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.forename: Jianyun
authors.initials: J
authors.lastname: Deng
authors.forename: Likun
authors.initials: L
authors.lastname: Zhang
authors.forename: Zhenjian
authors.initials: Z
authors.lastname: Du
authors.forename: Junjie
authors.initials: J
authors.lastname: Lu
authors.forename: Taiping
authors.initials: T
authors.lastname: Chen
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Wery
authors.forename: Yiyou
authors.initials: Y
authors.lastname: Chen
authors.forename: Qixiang
authors.initials: Q
authors.lastname: Li
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D044466:Asian People; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D000068818:Cetuximab; D000077547:Crizotinib; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D017354:Point Mutation; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D059467:Transcriptome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011720:Pyrazoles; D011725:Pyridines; D011799:Quinazolines; D000077547:Crizotinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D000068818:Cetuximab