A comprehensive review of targeting RAF kinase in cancer

Abstract

RAF kinases, particularly the BRAF isoform, play a crucial role in the MAPK/ERK signaling pathway, regulating key cellular processes such as proliferation, differentiation, and survival. Dysregulation of this pathway often caused by mutations in the BRAF gene or alterations in upstream regulators like Ras and receptor tyrosine kinases contributes significantly to cancer development. Mutations, such as BRAF-V600E, are present in a variety of malignancies, with the highest prevalence in melanoma. Targeted therapies against RAF kinases have achieved substantial success, especially in BRAF-V600E-mutant melanomas, where inhibitors like vemurafenib and dabrafenib have demonstrated remarkable efficacy, leading to improved patient outcomes. These inhibitors have also shown clinical benefits in cancers such as thyroid and colorectal carcinoma, although to a lesser extent. Despite these successes, therapeutic resistance remains a major hurdle. Resistance mechanisms, including RAF dimerization, feedback reactivation of the MAPK pathway, and paradoxical activation of ERK signaling, often lead to diminished efficacy over time, resulting in disease progression or even secondary malignancies. In response, current research is focusing on novel therapeutic strategies, including combination therapies that target multiple components of the pathway simultaneously, such as MEK inhibitors used in tandem with RAF inhibitors. Additionally, next-generation RAF inhibitors are being developed to address resistance and enhance therapeutic specificity. This review discusses the clinical advancements in RAF-targeted therapies, with a focus on ongoing efforts to overcome therapeutic resistance and enhance outcomes for cancer patients. It also underscores the persistent challenges in effectively targeting RAF kinase in oncology.