RTKs (receptor tyrosine kinases) and the RTK signaling pathways play an important role in cellular processes. The oncogenic activation of specific RTKs is the molecular target in advanced non-small cell lung cancer. Entrectinib is a multiple target inhibitor of TrkA, TrkB, TrkC, ROS1 and ALK inhibitor with IC50 values of 1.7, 0.1, 0.1, 0.2 and 1.6nM, respectively. Entrectinib exhibited in vitro anti-proliferative activity with IC50 value of 17nM in KM-12, a human colorectal cancer cell line driven by constitutively active TrkA fusion TPM3-NTRK1, accompanied by inhibition on p-TrkA and the inactivation of its downstream effectors, p-PLCγ1, p-AKT and p-ERK at dose of 10-250nM in 2h, as well as cell cycle arrest and apoptosis. Different manners in oral treatment with Entrectinib, including RXDX-101 at dose 15, 30 and 60mg/kg, BID for 10 days, 15mg/kg BID with 4 days on/ 3 days off for 3 cycles, and 15mg/kg continuously for 3 weeks, resulted in tumor regression and durable stasis in mice bearing KM-12 xenografts, accompanied by sustained intratumoral inhibition of p-TrkA and p-PLCγ1. These suggest that Entrectinib may be a promising therapeutic agent for patients with oncogenic Trk alterations[1].
作用机制
Entrectinib is an ATP-competitive inhibitor of the tyrosine kinases TrkA, TrkB, TrkC, ROS1, and ALK.[1]
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