TY - JOUR
T1 - Identification of existing drugs that effectively target NTRK1 and ROS1 rearrangements in lung cancer
AU - Chong, Curtis R.
AU - Bahcall, Magda
AU - Capelletti, Marzia
AU - Kosaka, Takayuki
AU - Ercan, Dalia
AU - Sim, Taebo
AU - Sholl, Lynette M.
AU - Nishino, Mizuki
AU - Johnson, Bruce E.
AU - Gray, Nathanael S.
AU - Jänne, Pasi A.
N1 - Funding Information:
R01CA1352571K23CA157631M. Nishino is a consultant/advisory board member for Bristol-Myers Squibb. B.E. Johnson has ownership interest (including patents) in KEW Group, is a consultant/advisory board member for AstraZeneca, Chugai, Clovis, Eli Lilly, KEW Group, Merck, Novartis, and Transgenomics, has provided expert testimony for Genentech and reports receiving post-marketing royalties for EGFR mutation testing from Dana-Farber Cancer Institute. P.A. Janne reports receiving commercial research grants from Astellas and AstraZeneca, has ownership interest (including patents) in Gatekeeper Pharmaceuticals, and is a consultant/advisory board member for AstraZeneca, Boehringer Ingelheim, Chugai, Clovis, Genentech, Merrimack Pharmaceuticals, Pfizer, and Sanofi, and reports receiving post-marketing royalties from Dana-Farber Cancer Institute owned intellectual property on EGFR mutations licensed to Lab Corp. No potential conflicts of interest were disclosed by the other authors. This study is supported by grants from the NIH RO1CA136851 (P.A. Jänne and N.S. Gray), R01CA135257 (P.A. Janne), 1K23CA157631 (M. Nishino) and 1 U54 HL127365-01 (N.S. Gray), the Cammarata Family Foundation Research Fund (M. Capelletti and P.A. Jänne), and the Nirenberg Fellowship at Dana-Farber Cancer Institute (M. Capelletti and P.A. Jänne). C.R. Chong is the recipient of funding from Uniting Against Lung Cancer, a Conquer Cancer Foundation/ASCO Young Investigator Award, and a post-doctoral fellowship from the American Cancer Society (PF-14-020-01-CDD). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85010223403&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-15-1601
DO - 10.1158/1078-0432.CCR-15-1601
M3 - Article
C2 - 27370605
AN - SCOPUS:85010223403
SN - 1078-0432
VL - 23
SP - 204
EP - 213
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -
