BRAF inhibitors elicit rapid antitumor responses in the majority of patients 
with BRAF(V600)-mutant melanoma, but acquired drug resistance is almost 
universal. We sought to identify the core resistance pathways and the extent of 
tumor heterogeneity during disease progression. We show that mitogen-activated 
protein kinase reactivation mechanisms were detected among 70% of 
disease-progressive tissues, with RAS mutations, mutant BRAF amplification, and 
alternative splicing being most common. We also detected 
PI3K-PTEN-AKT-upregulating genetic alterations among 22% of progressive 
melanomas. Distinct molecular lesions in both core drug escape pathways were 
commonly detected concurrently in the same tumor or among multiple tumors from 
the same patient. Beyond harboring extensively heterogeneous resistance 
mechanisms, melanoma regrowth emerging from BRAF inhibitor selection displayed 
branched evolution marked by altered mutational spectra/signatures and increased 
fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF 
inhibitor treatment failure, implying upfront, cotargeting of two core pathways 
as an essential strategy for durable responses.