To expand the possibilities to understand the molecular intricacies of unconventional pathways activated by oncogenic GNAQ, we focused our current studies on the hypothetical role of PDZ-RhoGEF/RhoJ as a direct signaling axis activated by Gαq Q209L, an oncogenic mutant, and used a rational data mining strategy, focusing on their relational signaling partners in cancer patients, to highlight those that, according to synthetic lethality datasets of cancer cells, represent vulnerabilities. The gene discussed is RHOJ; the disease is cancer.