BACKGROUND: Acquired resistance to @entity817 inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance. METHODS: We compiled clinical and genetic data from 100 @entity1 with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole-exome sequencing and/or polymerase chain reaction-based genetic testing. RESULTS: Among 132 samples, putative resistance mechanisms were identified in 58%, including @entity8497 or @entity984 mutations (20%), @entity817 splice variants (16%), @entity817 ( @entity8554 /K) amplifications (13%), @entity16629 mutations (7%), and non-mitogen-activated protein kinase pathway alterations (11%). Marked heterogeneity was observed within @entity5 and @entity1 ; 18 of 19 @entity1 (95%) with more than one progression biopsy had distinct/unknown drivers of resistance between samples. @entity8497 mutations were associated with @entity5457 use (p  =  0.045) and intracranial @entity3 (p  =  0.036), and @entity16629 mutations correlated with hepatic progression (p  =  0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent @entity817 and @entity8047 inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi-resistance mechanisms. CONCLUSIONS: This is the first study to systematically characterise the clinical implications of particular acquired BRAFi-resistance mechanisms in @entity1 with @entity817 -mutant @entity320 largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within @entity1 , @entity8497 mutations correlated with @entity5457 use and intracranial disease involvement.

Acquired XXXX inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms.

@entity1 :: ('9606', 'Species') :: ['patients'] @entity8047 :: ('5609', 'Gene') :: ['MEK'] @entity984 :: ('3845', 'Gene') :: ['KRAS'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumors'] @entity16629 :: ('5604;5605', 'Gene') :: ['MEK1/2'] @entity8554 :: ('p|SUB|V|600|E', 'ProteinMutation') :: ['V600E'] @entity8497 :: ('4893', 'Gene') :: ['NRAS'] @entity3 :: ('MESH:D009362', 'Disease') :: ['metastases'] @entity817 :: ('673', 'Gene') :: ['BRAF'] @entity320 :: ('MESH:D008545', 'Disease') :: ['melanoma'] @entity5457 :: ('MESH:C551177', 'Chemical') :: ['vemurafenib']
@entity817 :: (673,Gene) :: ['BRAF']
