Targeting BRAF Mutations: The Therapeutic Potential of CFT1946 in Preclinical Cancer Models

The BRAF enzyme plays a significant role in the MAPK pathway, with mutations found in about 8% of various cancers such as melanoma, thyroid, and lung adenocarcinoma. The V600E mutation is prevalent, particularly in melanoma, and leads to heightened ERK activity. While BRAF inhibitors like vemurafenib, dabrafenib, and encorafenib have shown success, resistance issues arise within a year through mechanisms like RAS mutation or BRAF amplification. These drugs also do not affect non-V600 BRAF mutations.

To overcome these challenges, CFT1946 has been developed as a BiDAC degrader that targets the BRAF kinase domain and cereblon ligand. It can degrade multiple BRAF mutations, including V600E, G469A, G466V, and the p61-BRAF splice variant, while being selective against the proteome. In cell studies, CFT1946 effectively degraded BRAF V600E, inhibiting ERK phosphorylation and cell growth, and showed no effect on KRAS-driven cells.

In animal models, oral CFT1946 induced significant tumor regression, outperforming a standard dose of encorafenib. It was also effective against a resistant BRAF V600E/NRAS Q61K double mutant model, where it degraded BRAF V600E and significantly inhibited cell viability compared to encorafenib. CFT1946, combined with the MEK inhibitor trametinib, resulted in tumor regressions, unlike the combination of encorafenib and trametinib.

Further studies showed that CFT1946 can degrade additional BRAF mutant proteins and inhibit the proliferation of a BRAF G466V heterozygous lung tumor cell line. Due to its effectiveness in preclinical models and drug-like properties, CFT1946 is being considered for clinical development for patients with solid tumors and BRAF V600X mutations. Its potential against non-V600 BRAF mutations is also being explored for therapeutic options for Class II or Class III BRAF mutations.