Tumor-Type Agnostic, Targeted Therapies: BRAF Inhibitors Join the Group

Abstract

In the present review, we briefly discuss the breakthrough advances in precision medicine using a tumor-agnostic approach and focus on BRAF treatment modalities, the mechanisms of resistance and the diagnostic approach in cancers with BRAF mutations. Tumor-type agnostic drug therapies work across cancer types and present a significant novel shift in precision cancer medicine. They are the consequence of carefully designed clinical trials that showed the value of tumor biomarkers, not just in diagnosis but in therapy guidance. Six tumor-agnostic drugs (with seven indications) have been approved through October 2022 by FDA. The first tumor-agnostic treatment modality was pembrolizumab for MSI-H/dMMR solid tumors, approved in 2017. This was followed by approvals of larotrectinib and entrectinib for cancers with NTRK fusions without a known acquired resistance mutation. In 2020, pembrolizumab was approved for all TMB-high solid cancers, while a PD-L1 inhibitor dostarlimab-gxly was approved for dMMR solid cancers in 2021. A combination of BRAF/MEK inhibitors (dabrafenib/trametinib) was approved as a tumor-agnostic therapy in June 2022 for all histologic types of solid metastatic cancers harboring BRAFV600E mutations. In September 2022, RET inhibitor selpercatinib was approved for solid cancers with RET gene fusions. CONCLUSION: Precision cancer medicine has substantially improved cancer diagnostics and treatment. Tissue type-agnostic drug therapies present a novel shift in precision cancer medicine. This approach rapidly expands to provide treatments for patients with different cancers harboring the same molecular alteration.

Keywords: BRAF; BRAF Inhibitors; Molecular Diagnostics; Precision Medicine; Targeted Therapy.

Figure 1

Schematic of MAPK signal (black/dark blue) and related (gray) pathways. Wild type BRAF (in dark blue) acts as a dimer (with BRAF or CRAF) to activate MEK in response to activation of RAS, eventually leading to cell proliferation. BRAF mutations (light blue) may act in a RAS-independent manner as monomers (Class I) or dimers (Class II), or in a RAS-dependent manner as a dimer (with wild type BRAF/CRAF). Mutant BRAF (in light blue) appears to be a stronger activator of MEK than wild type, with Class III less strong than classes I and II. BRAF inhibitor resistance may involve mutations at several of the genes encoding the proteins shown (see text).

Figure 2A-B

(A): Hematoxylin and Eosin (H&E) slide of a case of hairy cell leukemia with a diffuse bone marrow infiltration (10x magnification); neoplastic cells harbored BRAFV600E mutation, which was confirmed immunohistochemically using VE1 antibody (40x magnification).