Data from Cabozantinib Overcomes Crizotinib Resistance in ROS1 Fusion–Positive Cancer

作者：Ryohei Katayama, Yuka Kobayashi, Luc Friboulet, Elizabeth L. Lockerman, Sumie Koike, Alice Tsang Shaw, Jeffrey A. Engelman, Naoya Fujita · 年份：2023 · DOI：10.1158/1078-0432.c.6523104 · 被引用次数：1 · 研究领域：Lung Cancer Treatments and Mutations、Acute Lymphoblastic Leukemia research、Cancer therapeutics and mechanisms

Abstract 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. 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. 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...