Details

Autor(en) / Beteiligte

• Konicek, Bruce W
• Capen, Andrew R
• Credille, Kelly M
• Ebert, Philip J
• Falcon, Beverly L
• Heady, Gary L
• Patel, Bharvin K R
• Peek, Victoria L
• Stephens, Jennifer R
• Stewart, Julie A
• Stout, Stephanie L
• Timm, David E
• Um, Suzane L
• Willard, Melinda D
• Wulur, Isabella H
• Zeng, Yi
• Wang, Yong
• Walgren, Richard A
• Betty Yan, Sau-Chi

Titel

Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors

Ist Teil von

• Oncotarget, 2018-03, Vol.9 (17), p.13796-13806

Ort / Verlag

United States: Impact Journals

Erscheinungsjahr

2018

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Merestinib is an oral multi-kinase inhibitor targeting a limited number of oncokinases including MET, AXL, RON and MKNK1/2. Here, we report that merestinib inhibits neurotrophic receptor tyrosine kinases NTRK1/2/3 which are oncogenic drivers in tumors bearing NTRK fusion resulting from chromosomal rearrangements. Merestinib is shown to be a type II NTRK1 kinase inhibitor as determined by x-ray crystallography. In KM-12 cells harboring fusion, merestinib exhibits potent p-NTRK1 inhibition by western blot and elicits an anti-proliferative response in two- and three-dimensional growth. Merestinib treatment demonstrated profound tumor growth inhibition in cancer models harboring either a or an gene fusion. To recapitulate resistance observed from type I NTRK kinase inhibitors entrectinib and larotrectinib, we generated NIH-3T3 cells exogenously expressing wild-type, or acquired mutations G595R and G667C and . Merestinib blocks tumor growth of both wild-type and mutant G667C expressing NIH-3T3 cell-derived tumors. These preclinical data support the clinical evaluation of merestinib, a type II NTRK kinase inhibitor (NCT02920996), both in treatment naïve patients and in patients progressed on type I NTRK kinase inhibitors with acquired secondary G667C mutation in NTRK fusion bearing tumors.