Inhibition of anti-apoptotic BCL2 overcomes adaptive resistance to co-targeting of the protein kinase FAK and MEK in GNAQ-driven uveal melanoma.

ABSTRACT: Uveal melanoma (UVM) is the most common eye cancer in adults, with 50% of patients developing overt metastasis that often proves fatal. The majority of UVM harbor mutations in GNAQ or GNA11, encoding constitutively active Gαq proteins. Combined inhibition of MEK and FAK downstream of Gαq has shown promising effects in UVM cells by inducing apoptotic cell death, but resistance to this strategy can occur in the clinic. Here, we aimed to identify new targets to overcome resistance to MEK + FAK inhibition (FAKi + MEKi). Reverse-phase protein array (RPPA) analysis in UVM cells treated with FAKi + MEKi showed increased levels of pro-apoptotic proteins, such as PUMA and BIM, which promoted cell death. However, we observed an adaptive increase in anti-apoptotic proteins, including BCL2, upon FAK +

SUBMITTER: Lubrano S 

PROVIDER: S-EPMC12557573 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature