Reference Detail

Ref Type

Journal Article

PMID

(27370605)

Authors

Chong CR, Bahcall M, Capelletti M, Kosaka T, Ercan D, Sim T, Sholl LM, Nishino M, Johnson BE, Gray NS, Jänne PA

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	23	1	2017 Jan 01	204-213	Clin Cancer Res

URL

Abstract Text

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.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.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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Cabozantinib	Cabozantinib	25	90

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Cabozantinib	Cometriq	Cabometyx\|Cabozantinib-s-malate\|XL184	AXL Inhibitor 30 FLT3 Inhibitor 65 KIT Inhibitor 57 MET Inhibitor 59 RET Inhibitor 52 ROS1 Inhibitor 20 VEGFR2 Inhibitor 37	Cometriq (Cabometyx, cabozantinib) inhibits several receptor tyrosine kinases, including VEGFR2, FLT3, AXL, MET, RET, ROS1 fusions, and c-KIT (PMID: 27370605, PMID: 21926191). Cometriq (cabozantinib) is FDA approved for use in patients with medullary thyroid cancer, Cabometyx (cabozantinib) is FDA approved for use in patients with advanced renal cell carcinoma, hepatocellular carcinoma previously treated with sorafenib, adult and pediatric patients 12 years and older with locally advanced or metastatic differentiated thyroid cancer, and in combination with Opdivo (nivolumab) in patients with advanced renal cell carcinoma (FDA.gov).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References