Study reveals resistance mechanisms and potential treatment strategy for anaplastic thyroid cancer using type II RAF inhibitors

Summary

This study investigates resistance mechanisms to MAPK inhibition in anaplastic thyroid cancer (ATC), a highly lethal cancer. Using multi-region whole-genome, whole-exome, and single-nuclei RNA sequencing of tumors from ATC patients undergoing type I RAF inhibitor and MEK inhibitor therapy, the researchers found that MAPK pathway reactivation and immunosuppressive macrophage proliferation drive acquired resistance. The study demonstrates that naporafenib (a type II RAF inhibitor) combined with trametinib can overcome resistance to clinically approved RAF/MEK inhibitors, though acquired resistance to naporafenib occurs through compensatory MAST1 mutations. This translational genomics work provides a rationale for clinical investigation of type II RAF inhibitors in ATC.

Source

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