Combined Inhibition of MNK Signaling and BET Proteins Reveals TGM2 as a Novel Vulnerability in Melanoma

Melanoma is the deadliest form of skin cancer. MAPK-targeted therapies (MAPKi) and immune checkpoint inhibitors (ICI) have shown clinical benefit but are limited by resistance mechanisms that remain poorly defined. MNK1/2 inhibitors (MNKi) have shown promising effects in pre-clinical tumor models, particularly in melanoma. Herein, we find that bromodomain and extra-terminal domain protein inhibitors (BETi) in combination with MNKi reduce the proliferation of melanoma cells, including cells with acquired MAPKi resistance. Transcriptomic and proteomic analyses reveal that tissue transglutaminase TGM2 and inhibition of FAK activation are downstream effectors of this combination. We further demonstrate that TGM2 is overexpressed in MAPKi-resistant melanoma cells and that silencing TGM2 inhibits the proliferation of therapy-resistant melanoma cells. Our results introduce TGM2 as a new vulnerability in therapy-resistant melanoma development and suggest that a combination of MNKi and BETi may address the clinical need for novel therapies targeting unresponsive and drug-resistant melanoma.