Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Chromosomal rearrangements activate ALK and ROS1 tyrosine kinases in cancers like non-small cell lung cancer (NSCLC).
• TRK kinase rearrangements are increasingly identified in various solid tumors, presenting therapeutic opportunities.

Purpose of the Study:

• To report the discovery and preclinical characterization of entrectinib, a novel inhibitor of ALK, ROS1, and TRK kinases.
• To evaluate the efficacy of entrectinib in preclinical cancer models and assess its potential as a targeted cancer therapy.

Main Methods:

• Proliferation profiling of entrectinib against over 200 human tumor cell lines.
• In vivo studies involving oral administration of entrectinib to tumor-bearing mice with human xenograft tumors.
• Evaluation of entrectinib's activity in ALK-, ROS1-, and TRK-dependent tumor models, including brain metastases.

Main Results:

• Entrectinib demonstrated potent in vitro activity against cell lines dependent on its targeted kinases.
• Oral entrectinib induced regression in various human xenograft tumors, including TRKA-dependent colorectal carcinoma, ROS1-driven tumors, and ALK-dependent lung cancer brain metastases.
• Entrectinib is showing promising results in early-phase clinical trials, with objective responses observed in colorectal carcinoma and NSCLC.

Conclusions:

• Entrectinib is a potent inhibitor of ALK, ROS1, and TRK kinases with significant preclinical efficacy.
• Entrectinib shows therapeutic potential for a range of molecularly defined cancers, particularly TRK-dependent tumors.
• The drug is well-suited for treating cancers with oncogenic forms of ALK, ROS1, or TRK kinases, addressing an unmet need for TRK-inhibitor therapies.