Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer.

Content Provider	Semantic Scholar
Author	Katayama, Ryohei Kobayashi, Yuka Friboulet, Luc Lockerman, Elizabeth Koike, Sumie Shaw, Alice Tsang Engelman, Jeffrey A. Fujita, Naoya
Copyright Year	2015
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 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. 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.
File Format	PDF HTM / HTML
DOI	10.1158/1078-0432.CCR-14-1385
PubMed reference number	25351743
Journal	Medline
Volume Number	21
Issue Number	1
Alternate Webpage(s)	http://clincancerres.aacrjournals.org/content/clincanres/21/1/166.full.pdf
Alternate Webpage(s)	https://doi.org/10.1158/1078-0432.CCR-14-1385
Journal	Clinical cancer research : an official journal of the American Association for Cancer Research
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article