Acquired Secondary RAS Mutation in BRAF^V600E-Mutated Thyroid Cancer Patients Treated with BRAF Inhibitors

The BRAF^V600E mutation is the most common driver mutation in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC). This mutation is considered actionable and, for BRAF^V600E-mutated ATC, a BRAF inhibitor (dabrafenib) in combination with an MEK inhibitor (trametinib) is FDA approved. BRAF inhibitors have also shown efficacy in BRAF^V600E-mutated PTC. However, as with all targeted therapies, resistance to these drugs eventually develops. It is essential that we understand the mechanisms of resistance to the BRAF inhibitors in thyroid cancer to develop future strategies to effectively treat these patients and improve survival. Herein, we describe four patients with thyroid cancer treated with selective BRAF inhibitors, who developed a RAS mutation in addition to the BRAF^V600E mutation at progression. Patients 1 and 3 acquired a KRAS^G12V mutation in the progressive tumor, patient 2 acquired a NRAS^Q61K mutation in a progressive lymph node, and patient 4 acquired NRAS^G13D mutation on liquid biopsy performed at the time of radiographic disease progression. Similar to the melanoma experience, the emergence of RAS mutations appears to act as a mechanism of resistance to BRAF inhibitors in thyroid cancers.