BLU-667: A Promising Targeted Therapy for RET-Driven Cancers

The abstract discusses the development and evaluation of a new drug, BLU-667, which targets RET fusions and mutations prevalent in various cancer types. Initially identified in papillary thyroid cancer, RET fusions have been found in non-small cell lung adenocarcinoma and colorectal carcinoma. Activating mutations in RET are linked to multiple endocrine neoplasia and are common in medullary thyroid cancer. While multikinase inhibitors like cabozantinib and vandetanib are used to treat RET-altered tumors, their side effects can limit their effectiveness.

BLU-667 is designed to be a next-generation inhibitor that specifically targets activated forms of RET, showing high potency against both wild-type and mutant RET with a high degree of selectivity over other kinases like VEGFR-2. The drug was found to effectively inhibit RET autophosphorylation and cell proliferation in various cancer cell lines. In animal models, BLU-667 was well tolerated and showed dose-dependent inhibition of oncogenic RET kinase activity, including in models resistant to other inhibitors.

Importantly, BLU-667 was able to inhibit tumor growth without affecting VEGFR-2, indicating that selective RET inhibition is sufficient for antitumor activity. The drug's ability to spare off-target kinases suggests that it can inhibit RET at clinically achievable doses with fewer toxicities. BLU-667 also retains activity against mutations that confer resistance to other kinase inhibitors, which could prevent or delay the emergence of resistant cancer clones.

The drug is currently in a phase 1 clinical trial for patients with RET-driven solid tumors, offering a promising new treatment option for those with RET-altered cancers. The study was presented at the AACR-NCI-EORTC International Conference and published in the journal Molecular Cancer Therapeutics.