Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer.

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.

• Authors: Ryohei Katayama, Yuka Kobayashi, Luc Friboulet, Elizabeth L Lockerman, Sumie Koike, Alice T Shaw, Jeffrey A Engelman, Naoya Fujita
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 1 Pg. 166-74 (Jan 01 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25351743 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Anilides
• Antigens, Differentiation, B-Lymphocyte
• Histocompatibility Antigens Class II
• Oncogene Proteins, Fusion
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Pyrazoles
• Pyridines
• invariant chain
• cabozantinib
• Crizotinib
• Protein-Tyrosine Kinases
• ROS1 protein, human

Topics

• Anilides (administration & dosage)
• Antigens, Differentiation, B-Lymphocyte (biosynthesis, genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Crizotinib
• Drug Resistance, Neoplasm (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Histocompatibility Antigens Class II (biosynthesis, genetics)
• Humans
• Mutation
• Oncogene Proteins, Fusion (genetics)
• Protein Kinase Inhibitors (administration & dosage)
• Protein-Tyrosine Kinases (biosynthesis, genetics)
• Proto-Oncogene Proteins (biosynthesis, genetics)
• Pyrazoles (administration & dosage)
• Pyridines (administration & dosage)