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Clin Cancer Res. 2017 Jan 1;23(1):204-213. doi: 10.1158/1078-0432.CCR-15-1601. Epub 2016 Jul 1.

Identification of Existing Drugs That Effectively Target NTRK1 and ROS1 Rearrangements in Lung Cancer.

Author information

1
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
2
Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.
3
KU-KIST Graduate School of Converging Science and Technology, Seoul, Republic of Korea.
4
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
5
Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts, and Dana-Farber Cancer Institute, Boston, Massachusetts.
6
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. pasi_janne@dfci.harvard.edu Nathanael_Gray@dfci.harvard.edu.
7
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. pasi_janne@dfci.harvard.edu Nathanael_Gray@dfci.harvard.edu.
8
Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.

Abstract

PURPOSE:

Efforts to discover drugs that overcome resistance to targeted therapies in patients with rare oncogenic alterations, such as NTRK1 and ROS1 rearrangements, are complicated by the cost and protracted timeline of drug discovery.

EXPERIMENTAL DESIGN:

In an effort to identify inhibitors of NTRK1 and ROS1, which are aberrantly activated in some patients with non-small cell lung cancer (NSCLC), we created and screened a library of existing targeted drugs against Ba/F3 cells transformed with these oncogenes.

RESULTS:

This screen identified the FDA-approved drug cabozantinib as a potent inhibitor of CD74-ROS1-transformed Ba/F3, including the crizotinib-resistant mutants G2032R and L2026M (IC50 = 9, 26, and 11 nmol/L, respectively). Cabozantinib inhibited CD74-ROS1-transformed Ba/F3 cells more potently than brigatinib (wild-type/G2032R/L2026M IC50 = 30/170/200 nmol/L, respectively), entrectinib (IC50 = 6/2,200/3,500 nmol/L), and PF-06463922 (IC50 = 1/270/2 nmol/L). Cabozantinib inhibited ROS1 autophosphorylation and downstream ERK activation in transformed Ba/F3 cells and in patient-derived tumor cell lines. The IGF-1R inhibitor BMS-536924 potently inhibited CD74-NTRK1-transformed compared with parental Ba/F3 cells (IC50 = 19 nmol/L vs. > 470 nmol/L). A patient with metastatic ROS1-rearranged NSCLC with progression on crizotinib was treated with cabozantinib and experienced a partial response.

CONCLUSIONS:

While acquired resistance to targeted therapies is challenging, this study highlights that existing agents may be repurposed to overcome drug resistance and identifies cabozantinib as a promising treatment of ROS1-rearranged NSCLC after progression on crizotinib. Clin Cancer Res; 23(1); 204-13. ©2016 AACR.

PMID:
27370605
PMCID:
PMC5203969
DOI:
10.1158/1078-0432.CCR-15-1601
[Indexed for MEDLINE]
Free PMC Article

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