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Braf InhibitorsEdit

BRAF inhibitors are a class of targeted cancer therapies that block the kinase activity of BRAF, a protein in the MAPK signaling cascade that helps drive cell growth. These drugs are most impactful in tumors carrying activating alterations in BRAF, especially the V600E mutation, where signaling is constitutively on and fuels unchecked proliferation. In practice, BRAF inhibitors are often used in combination with other pathway inhibitors to extend responses and delay resistance. The development of these agents has been a clear example of how precision medicine can tailor treatment to a tumor’s genetic makeup, rather than using one-size-fits-all chemotherapy.

Mechanism of action

BRAF is part of the MAPK signaling pathway, which transmits signals from cell surface receptors to the nucleus to regulate growth and survival. When BRAF carries the V600E mutation, it remains constitutively active, driving continuous activation of downstream MEK and ERK proteins. BRAF inhibitors bind specifically to the mutated kinase, dampening this signaling and slowing tumor growth. However, in cells with normal (wild-type) BRAF, these drugs can paradoxically activate the pathway, potentially promoting new skin lesions such as keratoacanthomas or other cutaneous squamous cell carcinomas. This paradoxical activation arises from complex feedback and dimerization effects within the MAPK pathway and underpins both the clinical efficacy and some safety considerations of these agents. BRAF MAPK signaling pathway V600E mutation

Clinical uses

BRAF inhibitors are approved for tumors harboring activating BRAF mutations, with the most established benefit seen in melanoma. In melanoma, patients with BRAF V600 mutations often receive a BRAF inhibitor alone or, more commonly, in combination with a MEK inhibitor to improve outcomes and reduce adverse effects associated with paradoxical MAPK activation. Beyond melanoma, these agents have been studied and used in other cancers that carry BRAF V600 mutations, with varying degrees of success; approvals and guidelines have evolved as trial data have matured. For example, in non-small cell lung cancer with BRAF V600E mutations, combinations of a BRAF inhibitor with a MEK inhibitor have shown meaningful activity. In colorectal cancer, single-agent BRAF inhibition is generally ineffective due to compensatory signaling via EGFR, but combination strategies that include EGFR blockade have demonstrated activity in select settings. Other BRAF-mutant tumors, including certain thyroid cancers and rare hematologic cases, have also been treated with BRAF inhibitors in specific contexts or clinical trials. The goal in all settings remains the same: identify tumors driven by BRAF mutations and apply a therapy designed to interrupt that driver while managing resistance and safety. melanoma Non-small cell lung cancer Colorectal cancer thyroid cancer Vemurafenib Dabrafenib Encorafenib Trametinib Cobimetinib

Notable agents and combinations

  • Vemurafenib and dabrafenib are among the first BRAF inhibitors approved for BRAF-mutant melanoma, typically used with a MEK inhibitor to improve durability of response. Vemurafenib Dabrafenib Trametinib.
  • Encorafenib, another BRAF inhibitor, is approved for metastatic melanoma in combination with the MEK inhibitor binimetinib or with other partners in various regimens. Encorafenib Binimetinib.
  • Common strategy across indications is to combine a BRAF inhibitor with a MEK inhibitor to reduce paradoxical activation and improve progression-free and overall survival. Trametinib Cobimetinib Binimetinib.

Resistance and safety

Tumors often develop resistance to BRAF inhibitors through reactivation of the MAPK pathway or activation of alternative survival pathways. This has driven the standard practice of combining BRAF inhibitors with MEK inhibitors, which can delay resistance and mitigate some adverse events. Side effects are heterogeneous but can include skin-related lesions (e.g., keratoacanthomas and squamous cell carcinomas), fever and fatigue, rash, photosensitivity, and edema. Paradoxical activation in non-tumor cells explains some second-lesion risks and informs monitoring strategies. Ongoing research seeks to identify mechanisms of resistance and to refine combination regimens or sequencing with other therapies to extend benefit. drug resistance cutaneous squamous cell carcinoma paradoxical activation MAPK signaling pathway

Development, regulation, and policy considerations

The clinical introduction of BRAF inhibitors followed a rapid path from early-phase discovery to regulatory approvals driven by clear genotype–phenotype correlations. Companion diagnostic tests for BRAF mutations became central to identifying patients most likely to benefit, reflecting a broader shift toward precision medicine in oncology. As therapies matured, combination strategies that pair BRAF inhibitors with MEK inhibitors gained prominence, offering improved outcomes in several settings. The economics of these drugs—pricing, patient access, and reimbursement—have become a recurrent topic in health care policy debates, particularly given the high costs of targeted cancer therapies and the need for broad patient access within diverse health systems. Proponents of market-based approaches emphasize speed of innovation and patient choice, while critics point to the burden of cost and the importance of value-based pricing and patient protections. FDA companion diagnostic Pharmacoeconomics Drug pricing Health care policy Targeted therapy

See also