Cabozantinib Overcomes Crizotinib Resistance in ROS1 Fusion–Positive Cancer

DOI PDF PubMed 被引用文献12件 参考文献24件 オープンアクセス
  • Ryohei Katayama
    1Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • Yuka Kobayashi
    1Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • Luc Friboulet
    3Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
  • Elizabeth L. Lockerman
    3Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
  • Sumie Koike
    1Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • Alice T. Shaw
    3Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
  • Jeffrey A. Engelman
    3Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
  • Naoya Fujita
    1Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.

説明

<jats:title>Abstract</jats:title> <jats:p>Purpose: ROS1 rearrangement leads to constitutive ROS1 activation with potent transforming activity. In an ongoing phase I trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib shows remarkable initial responses in patients with non–small cell lung cancer (NSCLC) harboring ROS1 fusions; however, cancers eventually develop crizotinib resistance due to acquired mutations such as G2032R in ROS1. Thus, understanding the crizotinib-resistance mechanisms in ROS1-rearranged NSCLC and identification of therapeutic strategies to overcome the resistance are required.</jats:p> <jats:p>Experimental Design: The sensitivity of CD74–ROS1–transformed Ba/F3 cells to multiple ALK inhibitors was examined. Acquired ROS1 inhibitor–resistant mutations in CD74–ROS1 fusion were screened by N-ethyl-N-nitrosourea mutagenesis with Ba/F3 cells. To overcome the resistance mutation, we performed high-throughput drug screening with small-molecular inhibitors and anticancer drugs used in clinical practice or being currently tested in clinical trials. The effect of the identified drug was assessed in the CD74–ROS1–mutant Ba/F3 cells and crizotinib-resistant patient-derived cancer cells (MGH047) harboring G2032R-mutated CD74–ROS1.</jats:p> <jats:p>Results: We identified multiple novel crizotinib-resistance mutations in the ROS1 kinase domain, including the G2032R mutation. As the result of high-throughput drug screening, we found that the cMET/RET/VEGFR inhibitor cabozantinib (XL184) effectively inhibited the survival of CD74–ROS1 wild-type (WT) and resistant mutants harboring Ba/F3 and MGH047 cells. Furthermore, cabozantinib could overcome all the resistance by all newly identified secondary mutations.</jats:p> <jats:p>Conclusions: We developed a comprehensive model of acquired resistance to ROS1 inhibitors in NSCLC with ROS1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance. Clin Cancer Res; 21(1); 166–74. ©2014 AACR.</jats:p>

収録刊行物

  • Clinical Cancer Research

    Clinical Cancer Research 21 (1), 166-174, 2015-01-01

    American Association for Cancer Research (AACR)

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