Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy

By Hubing Shi, Willy Hugo, X. Kong, Aayoung Hong, R. Koya, G. Moriceau, T. Chodon, R. Guo, Douglas B. Johnson, K. Dahlman and 9 more. Cancer Discovery, 2013

925 citations recorded by the source corpus.

BRAF inhibitors elicit rapid anti-tumor responses in the majority of patients with V600BRAF 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 MAPK 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 re-growth 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, co-targeting of two core pathways as an essential strategy for durable responses.

Subfields: Molecular Biology, Oncology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/e640d2ddbe6fa658ae3359f510cf5ab5bb1fedd6

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Citations in the corpus

Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma (2016, positive): “We called single nucleotide variant (SNV) and small insertion-deletion (INDEL) as reported (Shi et al., 2014) using a stand-alone version of Oncotator (Ramos et al.”
Overcoming Endocrine Resistance in Breast Cancer (2020, positive): “, 2016), 2) target-independent activation of downstream or bypass signaling pathways (ie, RTK, PI3K, and MAPK pathway deregulation) (Arteaga and Engelman, 2014; Cocco et al., 2019; Hazar-Rethinam et al., 2018; Shi et al., 2014), and 3) microenvironmental components that affect drug sensitivity (Hira”
Spatial and temporal diversity in genomic instability processes defines lung cancer evolution (2014, background): “from R3 might be resistant due to the PIK3CA mutation (32).”
Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. (2014, neutral): “Photosensitivity reaction 25 (10) 12 (5) 0 0 48 (19) 18 (7) 6 (2) 0”
Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. (2014, neutral): “Complete response 22 (10) 18 (9) 19 (11) 16 (9) 3 (10) 2 (7)”
Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. (2017, positive): “For example, in 13/16 patients with BRAF-mutant melanomas with resistance to RAF inhibition, multiple parallel mechanisms of resistance were observed (Shi et al., 2014).”
Primary resistance to PD-1 blockade mediated by JAK1/2 mutations (2016, methodology): “Methods were modified from reference (39); specifically the substitution the GATK-HaplotypeCaller (HC, v3.”
Big data: the next frontier for innovation in therapeutics and healthcare (2014, background): “Investigators are able to access this information to analyze differential expression patterns [11] .”