Precision Targeted Therapy with BLU-667 for RET-Driven Cancers

by Selleckchem | Aug 22 2023

The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting.

Significance: Patients with RET-driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with RET mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with RET-altered tumors, clinically validating selective RET targeting.

Comments:

The information you provided highlights the significance of the receptor tyrosine kinase rearranged during transfection (RET) as an oncogenic driver in multiple cancers, such as non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. Currently, there are no approved therapies specifically designed to target RET, and treatment options have been limited to multikinase inhibitors (MKIs), which can have off-target toxicities and limited efficacy.

However, a potential breakthrough in RET-targeted therapy has been found with BLU-667. This compound is a highly potent and selective RET inhibitor that aims to overcome the limitations of existing treatments. In laboratory studies (in vitro), BLU-667 has demonstrated more than a 10-fold increase in potency compared to approved MKIs against oncogenic RET variants and resistance mutants.

In preclinical studies (in vivo), BLU-667 has shown potent inhibition of tumor growth in NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions. Importantly, BLU-667 achieved this without inhibiting VEGFR2, which is a common off-target effect associated with some MKIs.

The first-in-human testing of BLU-667 has shown promising results. It significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC. Notably, there were no notable off-target toxicities observed, further validating the selective targeting of RET.

This information underscores the significance of BLU-667 as a highly potent and selective RET inhibitor. It has demonstrated efficacy in preclinical models and has shown promising results in early clinical trials, providing validation for the selective targeting of RET in patients with RET-driven cancers. These findings suggest that BLU-667 may offer a more effective and less toxic treatment option for patients with RET-altered tumors.