Despite important advances in the treatment of metastatic
melanoma with the development of MAPK-targeted agents and
immune checkpoint inhibitors, the majority of patients either do not respond to
therapies or develop acquired resistance. Furthermore, there is no effective targeted
therapy currently available for BRAF wild-type
melanomas (approximately 50% of cutaneous
melanoma). Thus, there is a compelling need for new efficient targeted
therapies.
Prohibitins (PHBs) are overexpressed in several types of
cancers and implicated in the regulation of signaling networks that promote cell invasion and resistance to cell apoptosis. Herein, we show that PHBs are highly expressed in
melanoma and are associated with not only poor survival but also with resistance to BRAFi/MEKi. We designed and identified novel specific PHB inhibitors that can inhibit
melanoma cell growth in 3D spheroid models and a large panel of representative cell lines with different molecular subtypes, including those with intrinsic and acquired resistance to MAPKi, by significantly moderating both MAPK (CRAF-ERK axis) and PI3K/AKT pathways, and inducing apoptosis through the mitochondrial pathway and up-regulation of p53. In addition, autophagy inhibition enhances the antitumor efficacy of these PHB
ligands. More important, these
ligands can act in synergy with MAPKi to more efficiently inhibit cell growth and overcome drug resistance in both BRAF wild-type and mutant
melanoma. In conclusion, targeting PHBs represents a very promising therapeutic strategy in
melanoma, regardless of mutational status.