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

Authors

  • Mengmeng Yang,

    1. Crown Bioscience, Inc., 3375 Scott Blvd, suite 108, Santa Clara, CA 95054, USA
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    • Disclosure: M.Y., X.S., J.C., J.D., L.Z., Z.D., J.L., T.C., J.P.W., Y.C. and Q.L. are presently employees of Crown Bioscience, Inc. Y.C. is also a shareholder of Crown bioscience, Inc.

  • Baoen Shan,

    1. Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China, 050011
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  • Qiaoxia Li,

    1. Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China, 050011
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  • Xiaoming Song,

    1. Crown Bioscience, Inc., 3375 Scott Blvd, suite 108, Santa Clara, CA 95054, USA
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    • Disclosure: M.Y., X.S., J.C., J.D., L.Z., Z.D., J.L., T.C., J.P.W., Y.C. and Q.L. are presently employees of Crown Bioscience, Inc. Y.C. is also a shareholder of Crown bioscience, Inc.

  • Jie Cai,

    1. Crown Bioscience, Inc., 3375 Scott Blvd, suite 108, Santa Clara, CA 95054, USA
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    • Disclosure: M.Y., X.S., J.C., J.D., L.Z., Z.D., J.L., T.C., J.P.W., Y.C. and Q.L. are presently employees of Crown Bioscience, Inc. Y.C. is also a shareholder of Crown bioscience, Inc.

  • Jianyun Deng,

    1. Crown Bioscience, Inc., 3375 Scott Blvd, suite 108, Santa Clara, CA 95054, USA
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    • Disclosure: M.Y., X.S., J.C., J.D., L.Z., Z.D., J.L., T.C., J.P.W., Y.C. and Q.L. are presently employees of Crown Bioscience, Inc. Y.C. is also a shareholder of Crown bioscience, Inc.

  • Likun Zhang,

    1. Crown Bioscience, Inc., 3375 Scott Blvd, suite 108, Santa Clara, CA 95054, USA
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    • Disclosure: M.Y., X.S., J.C., J.D., L.Z., Z.D., J.L., T.C., J.P.W., Y.C. and Q.L. are presently employees of Crown Bioscience, Inc. Y.C. is also a shareholder of Crown bioscience, Inc.

  • Zhenjian Du,

    1. Crown Bioscience, Inc., 3375 Scott Blvd, suite 108, Santa Clara, CA 95054, USA
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    • Disclosure: M.Y., X.S., J.C., J.D., L.Z., Z.D., J.L., T.C., J.P.W., Y.C. and Q.L. are presently employees of Crown Bioscience, Inc. Y.C. is also a shareholder of Crown bioscience, Inc.

  • Junjie Lu,

    1. Crown Bioscience, Inc., 3375 Scott Blvd, suite 108, Santa Clara, CA 95054, USA
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    • Disclosure: M.Y., X.S., J.C., J.D., L.Z., Z.D., J.L., T.C., J.P.W., Y.C. and Q.L. are presently employees of Crown Bioscience, Inc. Y.C. is also a shareholder of Crown bioscience, Inc.

  • Taiping Chen,

    1. Crown Bioscience, Inc., 3375 Scott Blvd, suite 108, Santa Clara, CA 95054, USA
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    • Disclosure: M.Y., X.S., J.C., J.D., L.Z., Z.D., J.L., T.C., J.P.W., Y.C. and Q.L. are presently employees of Crown Bioscience, Inc. Y.C. is also a shareholder of Crown bioscience, Inc.

  • Jean-Pierre Wery,

    1. Crown Bioscience, Inc., 3375 Scott Blvd, suite 108, Santa Clara, CA 95054, USA
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    • Disclosure: M.Y., X.S., J.C., J.D., L.Z., Z.D., J.L., T.C., J.P.W., Y.C. and Q.L. are presently employees of Crown Bioscience, Inc. Y.C. is also a shareholder of Crown bioscience, Inc.

  • Yiyou Chen,

    1. Crown Bioscience, Inc., 3375 Scott Blvd, suite 108, Santa Clara, CA 95054, USA
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    • Disclosure: M.Y., X.S., J.C., J.D., L.Z., Z.D., J.L., T.C., J.P.W., Y.C. and Q.L. are presently employees of Crown Bioscience, Inc. Y.C. is also a shareholder of Crown bioscience, Inc.

  • Qixiang Li

    Corresponding author
    1. Crown Bioscience, Inc., 3375 Scott Blvd, suite 108, Santa Clara, CA 95054, USA
    2. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China, 100191
    • Crown Bioscience, Inc., 3375 Scott Blvd, suite 108, Santa Clara, CA 95054, USA
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    • Disclosure: M.Y., X.S., J.C., J.D., L.Z., Z.D., J.L., T.C., J.P.W., Y.C. and Q.L. are presently employees of Crown Bioscience, Inc. Y.C. is also a shareholder of Crown bioscience, Inc.


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.

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