BRAF

  • V-RAF murine sarcoma viral oncogene homolog B1 (BRAF)
  • Gene Location: chromosome 7 (7q34)

BRAF Biology

  • The BRAF gene is located on chromosome 7, and its corresponding protein plays a role in the RAS-RAF-MEK-ERK (MAPK) signal transduction pathway.1-5
  • MAPK enzymes are activated through interaction with growth factors, cytokines, and hormones.4
  • More than a dozen known MAPK enzymes regulate cell differentiation, proliferation, and survival.4,5
  • BRAF and its family of proteins are serine/threonine kinases that target other MAPK proteins via phosphorylation.4,5
  • BRAF has 3 conserved regions (CRs) involved in protein function: CR1, CR2, and CR3.6
  • CR1 and CR3 interact to form an autoinhibitory complex, whereas CR2 functions as a hinge for this complex.6
  • Under normal conditions, RAS-GTP binds the CR1-CR3 complex and exposes the CR3 catalytic site for substrate activation.6
  • Once activated, BRAF is localized to the cell membrane.4

Etiology and Epidemiology

  • BRAF is a major driver of gene alteration in many types of cancer, including pancreatic malignancies, and the V600E mutation has been best characterized as a constitutive active driver mutation.4,6
  • Mutated BRAF can create a constitutively active protein that drives unregulated cell growth and division.1,4,6
  • Pathogenic BRAF variants, including class I/II mutations, deletions, and fusions, are present in 2% to 4% of advanced pancreatic cancer cases, occurring more frequently in KRAS wild-type vs KRAS-mutant tumors (30% vs 1.5%, respectively).3,7
  • BRAF V600E comprise approximately 17-28% of BRAF mutations in pancreatic cancer.

BRAF V600E Testing

  • When to Test: Testing is recommended for patients with locally advanced or metastatic pancreatic cancer who are candidates for anticancer therapy.8
  • Available Testing Methods: BRAF testing can be performed using immunohistochemistry (IHC) or, preferably, next-generation sequencing (NGS).8
  • Guideline Recommendations for Testing: The National Comprehensive Cancer Network guidelines recommend testing for actionable somatic mutations including those involving BRAF for all patients with advanced pancreatic cancer regardless of the presence of metastases.8 The recommended testing method is NGS with an FDA-approved assay, although there is a growing consensus that RNA-based testing for fusion gene expression should be strongly considered as well.8

BRAF V600E Targeted Therapy

  • Approved Agents: The only FDA-approved treatment for BRAF V600E–mutant pancreatic cancer is dabrafenib plus trametinib.1,2,7
  • Mechanism of Action: Dabrafenib inhibits signals from the BRAF protein activated by the BRAF V600E mutation and prevents associated tumor growth.1 Trametinib complements this mechanism by inhibiting mitogen-activated extracellular-regulated kinase 1 (MEK1) and MEK2 that is activated by the mutated gene.2 The dual action prevents tumors from continuing to grow via the escape mechanism of MEK protein activating signals.9

Learn more about Dabrafenib and Trametinib >

References

  1. TAFINLAR (dabrafenib). Prescribing information. Novartis; 2024. Accessed March 11, 2024. https://www.novartis.com/us-en/sites/novartis_us/files/tafinlar.pdf
  2. MEKINIST (trametinib). Prescribing information. Novartis; 2024. Accessed March 11, 2024. https://www.novartis.com/us-en/sites/novartis_us/files/mekinist.pdf
  3. New study targets specific BRAF mutation. Let’s Win Pancreatic Cancer. July 27, 2023. Accessed March 11, 2024. https://letswinpc.org/research/target-braf-mutation/
  4. Wan PTC, Garnett MJ, Roe SM, et al; Cancer Genome Project. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116(6):855-867. doi:10.1016/s0092-8674(04)00215-6
  5. Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011;75(1):50-83. doi:10.1128/MMBR.00031-10
  6. Zaman A, Wu W, Bivona TG. Targeting oncogenic BRAF: past, present, and future. Cancers (Basel). 2019;11(8):1197. doi:10.3390/cancers11081197
  7. Allen MJ, Zhang A, Bavi P, et al. Molecular characterisation of pancreatic ductal adenocarcinoma with NTRK fusions and review of the literature. J Clin Pathol. 2023;76(3):158-165. doi: 10.1136/jclinpath-2021-207781.
  8. NCCN. Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, version 1.2024. Accessed June 11, 2024. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
  9. Winstead E. Dabrafenib-trametinib combination approved for solid tumors with BRAF mutations. American Cancer Society. July 21, 2022. Accessed March 9, 2024. https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-dabrafenib-trametinib-braf-solid-tumors