Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond

Abstract

The identification of mutationally activated BRAF in many cancers altered our conception of the role played by the RAF family of protein kinases in oncogenesis. In this review we describe the development of BRAF inhibitors and the results that have emerged from their analysis in both the laboratory and the clinic. We discuss the spectrum of RAF mutations in human cancer and the complex interplay between tissue of origin and response to RAF inhibition. Finally, we enumerate mechanisms of resistance to BRAF inhibition that have been characterized and postulate how strategies of RAF pathway inhibition may be extended in scope to benefit, not only the thousands of patients diagnosed annually with BRAF-mutated metastatic melanoma, but also the larger patient population with malignancies harboring mutationally activated RAF genes that is ineffectively treated with the current generation of BRAF kinase inhibitors.

Inhibition of Galectin-1 Sensitizes HRAS-driven Tumor Growth to Rapamycin Treatment

“…Development of anti-RAS therapeutic agents has turned towards targeting elements downstream of RAS, mainly either the PI3K or MAPK pathways (13)(14)(15). While several such approaches have been moderately effective, recent efforts have focused on preclinical evaluation of combination therapies.…”

“…This has prompted efforts at targeting RAS effectors, most notably in either the RAF/MEK/ERK or PI3K/AKT/mTOR pathways. MAPK-based inhibitors have encountered obstacles in reducing tumor burden, either as a result of paradoxical feedback loops which increase signaling, such as in the case of the RAF homology B (BRAF) inhibitor sorafenib, or innate/acquired resistance [for review see (15)]. A number of inhibitors targeting the PI3K/AKT/mTOR axis have been under evaluation, with varying efficiency.…”

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

“…It is worthy to note that sensitivity to BRAF inhibitors is not only dependent on presence of the activating mutation, but also of the tumor type under study 42,46,50,53,54 . For example, although the BRAF inhibitors have led to impressive advances in the treatment of melanoma, and some success in patients with BRAF-mutated NSCLC 55 , they seem to have a relative lack of efficacy in colorectal cancer, even in patients who have a BRAF V600E mutation 56,57 .…”

Ovarian carcinoma: An overview of current status

“…Although the use of FSS is very effective in preserving childbearing capacity, its application is controversial owing to the use of in vitro fertilization after surgery [97] . The use of BRAF inhibitors (vemurafenib and dabrafenib) and MEK inhibitor (trametinib) offers a more hopeful option for ovarian carcinoma patients and these inhibitors are also used in rational pathway-targeted therapeutic combinations such as co-targeting PI3-kinase signaling, as well as dosing strategies to prevent or delay drug resistance and achieve long-term survival benefit [98] . Poly(ADP-ribose) polymerase (PARP) inhibitors have been approved by the US Food and Drug Administration (FDA) as a monotherapy in patients previously treated with chemotherapy, and the inhibitors have also shown synergistic action with anti-angiogenic agents due to oxygenation changes.…”