Therapeutic Escape in Gαq-mutant Uveal Melanoma: It's a FAK

Abstract

Through a synthetic lethal screen, ERK activation was found to mediate resistance to FAK inhibition in GNAQ-mutant uveal melanoma. With PLCB-PKC-ERK and Trio-FAK-Yap representing compensatory effectors of mutant Gαq signaling, combined inhibition of both pathways may be a promising therapeutic strategy in metastatic uveal melanoma.See related article by Paradis et al., p. 3190.

FIGURE 1

Potential pharmacologic targets in metastatic uveal melanoma. Most uveal melanomas containing initiating mutation in a member of the Gα_q/11 pathway (GNAQ, GNA11, CYSLTR2, and PLCB4), which trigger oncogenic signaling through multiple effectors, including PKC-MEK, PI3K-AKT, and FAK-YAP. The data presented by Paradis and colleagues (1) identifies dual inhibition of MEK and FAK as a synergistic combination in preclinical models of uveal melanoma. Other work has shown that HDAC inhibitors may also increase the efficacy of MEK inhibitors by blocking AKT and YAP signaling (4). Gα_q/11 mutations result in benign melanocytic lesions unless additional genetic and genomic events occur. The mutations most strongly associated with metastasis in uveal melanoma occur in the metastasis suppressor BAP1, which are associated with extensive epigenetic and transcriptional rewiring that can be at least partly reversed by inhibition of HDAC activity. BAP1-mutant uveal melanomas are also enriched for exhausted cytotoxic T cells, alternatively activated macrophages, and other cells associated with immune dysfunction that likely contribute to metastatic competence and therapeutic resistance. LAG3 was recently shown to be a predominant checkpoint marker in uveal melanoma and its inhibition is currently the subject of a clinical trial in patients with metastatic uveal melanoma.