Though we cannot predict how such a wide array of HNSSC-associated MAPK pathway mutations may alter sensitivity and resistance to various agents, lessons from BRAF p.V600E-mutated melanomas and thyroid cancers do alert us of such possibility of resistance to long-term monotherapy treatment through reactivation of MEK/ERK signaling (and some other mechanisms including constitutive activation of EGFR and PI3K, etc.)93, which can be co-targeted by BRAF-MEK inhibitor combinations (e.g., encoragenib-binimetinib; dabrafenib-trametinib, etc) as approved recently by the FDA for other cancers. The gene discussed is BRAF; the disease is melanoma.