Promising Strategies for Overcoming BRAF Inhibitor Resistance Based on Known Resistance Mechanisms

Abstract

Background: Almost 50% of metastatic melanomas harbor BRAF mutations. Since 2011, BRAF inhibitors have exhibited striking clinical benefits in BRAF-mutant melanoma patients. Unfortunately, their therapeutic effects are often temporary. The resistance mechanisms vary and can be broadly classified as MAPK reactivationdependent and -independent. Elucidation of these resistance mechanisms provides new insights into strategies for overcoming resistance. Indeed, several alternative treatment strategies, including changes in the mode of administration, combinations of BRAF and MEK inhibitors, and immunotherapy have been verified as beneficial to BRAF inhibitor-resistant melanoma patients. Prospect: In this review, we discuss promising strategies for overcoming drug resistance and highlight the prospects for discovering strategies to counteract BRAF inhibitor resistance.

Melanoma: BRAFi Rechallenge

“…Therefore, having used the “powerful weapons” in the fight against melanoma, the management of this recurrence has raised concerns. Targeted therapy, which the patient had started years ago, was considered a good choice, as the tumor cell resistance mechanisms that may have formed may have been eliminated by stopping BRAFi and MEKi for a significant period of time [ 2 , 3 , 5 , 6 ].…”

The Evolution of BRAF Activation in Non-Small-Cell Lung Cancer

“…For example, FDA has approved the combination of BRAF inhibitors (Vemurafenib and Dabrafenib) and MEK inhibitor trametinib for the treatment of BRAF inhibition resistance. And clinical studies of PI3K/AKT inhibitor plus MAPK inhibitor, everolimus (RAD001) plus bevacizumab, everolimus (RAD001) plus temozolomide (TMZ), and targeted therapy plus immunotherapy have also been conducted, but there is a lack of more data to support these therapies, so further exploration is needed ( 82 ). The strategies for resistance to BRAF inhibitors were listed in Table 1 .…”