Resistance to BRAF inhibitors: unraveling mechanisms and future treatment options

Abstract

The mitogen-activated protein kinase (MAPK) pathway has emerged as a central target for melanoma therapy due to its persistent activation in the majority of tumors. Several BRAF inhibitors aimed at curbing MAPK pathway activity are currently in advanced stages of clinical investigation. However, their therapeutic success is limited by the emergence of drug resistance, as responses are transient and tumors eventually recur. To develop effective and long-lasting therapies for melanoma patients, it is essential to understand the mechanisms underlying resistance to BRAF inhibitors. Here, we briefly review recent preclinical studies that have provided insight into the molecular mechanisms of resistance to BRAF inhibitors and discuss potential strategies to treat drug-resistant melanomas.

Figure 1

Simplified schematic of signaling pathways driving resistance to BRAF inhibitors. In BRAF V600E mutant melanoma cells (left), BRAF inhibition causes growth arrest and apoptosis by blocking the MAPK pathway. These BRAF-inhibitor (BRAFi-) sensitive cells are highly dependent on BRAF for MAPK activation and survival. Following chronic BRAF inhibition, resistant cells (right) evolve an array of compensatory mechanisms, including RAF isoform switching, activation of RTKs such as IGF-1R, and engagement of the PI3K pathway to promote cell survival. PTEN loss leads to activation of the PI3K pathway. Understanding the signaling networks that drive drug resistance will enable the development of rational drug combinations to target melanomas refractory to BRAF inhibitors. Also shown are inhibitors that can be used to block the compensatory pathways identified so far.