Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma
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Genomic diversity and adaptive plasticity of melanoma tumors limit durable control with conventional and targeted therapies. Nevertheless, pathological activation of the ERK1/2 regulatory system is a linchpin tumorigenic mechanism associated with the majority of both primary and recurrent disease. To avoid common resistance mechanisms associated with perdurance of ERK1/2 signaling, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathological ERK1/2 signaling. Such targets could be leveraged in jiu jitsu fashion to breach selective pressure to engage any of the many BRAF-independent ERK1/2 pathway activation mechanisms. By integration of multi-genome chemical and genetic screens; recurrent architectural variants in melanoma tumor genomes; and patient outcome data; we identified 2 mechanistic subtypes of BRAF(V600) melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKE inhibitors. Importantly, subtype membership can be predicted using a robust quantitative 5-feature genetic biomarker. This biomarker, or the mechanistic relationships linked to it, can identify a cohort of best responders to clinical MEK inhibitors (detectable in 25% of melanoma patients) and identify a cohort of TBK1/IKBKE inhibitor-sensitive disease among non-responders to current targeted therapy (detectable in 9.9% of melanomas).