The inhibition of three distinct signaling pathways eliminates the oncogenic Tribbles homolog 2 from melanoma cells

Tribbles homolog 2 (TRIB2) is one of three members of the Tribbles family of pseudo serine/threonine kinases. It acts as an oncogene whose expression is correlated with tumor stage and therapy response in melanoma. While metastatic melanoma, the most aggressive form of skin cancer now has two effective treatment options, namely MAPK pathway and immune checkpoint inhibitors, the majority of patients primarily fail to respond or acquire secondary resistance. Hence, innovative approaches to identify disease-relevant, druggable targets to remove the roadblock of therapy resistance are urgently needed. TRIB2 has been implicated in conferring resistance to various anti-cancer therapies suggesting TRIB2 as a therapeutic target for resistant tumors. This study explores the pharmacological targeting of TRIB2, revealing several independent routes of pharmacological manipulations. TRIB2 is a short-lived protein stabilized by inhibition of the PI3K/AKT pathway. Conversely, inhibitors of BRAF, MEK and ERK significantly decrease TRIB2 expression by a mechanism that involves transcription. Strikingly, increasing concentrations of the kinase inhibitor PIK75 effectively eliminate TRIB2 in melanoma cells surpassing its PI3K inhibitory activity. Additionally, Polo-Like Kinases (PLKs) inhibitors significantly reduce TRIB2 protein expression and stability. We demonstrate that inhibition or silencing of PLK2 leads to a decrease in TRIB2 levels. Overall, we identify three distinct classes of compounds that efficiently eliminate the oncogenic TRIB2 protein from melanoma cells based on different molecular mechanisms and exhibiting 40 to 200 times greater potency than the previously reported afatinib.