Abstract
Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a “precision medicine” paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies.
Highlights
During transformation, cancer cells accumulate many genetic and epigenetic alterations [1]
The Cancer Genome Atlas (TCGA) is a large-scale multi-omics effort that has led to comprehensive analysis and identification of novel molecular alterations, which classify tumors into distinct subclasses for therapy and predict therapy response [6,7]
We focus on the role of BRAF as an oncogene
Summary
Cancer cells accumulate many genetic and epigenetic alterations [1]. 1970s and 1980s, building on the discovery of the proto-oncogene Src and tumor suppressor Rb, many of such core molecular aberrations of cancers were identified [2,3]. The Cancer Genome Atlas (TCGA) is a large-scale multi-omics effort that has led to comprehensive analysis and identification of novel molecular alterations, which classify tumors into distinct subclasses for therapy and predict therapy response [6,7]. In non-small cell lung cancer (NSCLC), a staggering ≈60% of the tumors had alterations in chief “driver oncogenes” including EGFR, BRAF, and KRAS combined [11,12,13]. A number of multi-omics studies have revealed the heterogeneity and complexities of the cancer genomic landscape, and the dynamic nature of the therapy-driven tumor evolution. We summarize recent developments of, and prospects for, genomics-guided personalized therapy approaches in BRAF-mutant tumors in the light of the complexities of tumor biology and evolution
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