Targeting YAP/TAZ-tead activity in drug-tolerant aged melanoma

Abstract

Melanoma is the most lethal type of skin cancer because it is more metastatic and has a high rate of resistance to conventional therapies, which results in a worse prognosis, especially in the elderly. About 50% of melanoma casa involve a mutation in the BRAF gene, in which valine is replaced by glutamic acid at codon 600. In melanoma there is a reduction in Hippo pathway signaling and this is associated with increased tumor formation and metastasis. The Hippo signaling pathway proteins YAP/TAZ are important drivers of melanoma. In addition to the tumor process, YAP/TAZ activity decreases with aging. The TEAD family of transcription factors has been identified as key partners of YAP/TAZ in driving cancer progression and survival. Thus, it is possible that the inhibition of the YAP/TAZ-TEAD interaction is a viable therapeutic strategy against melanoma. To evaluate this, human skin aged by glycation associated with melanoma will be reconstructed, which has already obtained preliminary results that showed that aging associated with resistant melanoma presented more tumor invasion and inflammation. Therefore, we intend to explore whether the new TEAD inhibitors VT103 and VT107 can improve the effectiveness of combined targeted BRAFI/MEKi therapy for BRAFV600 melanoma in vitro and in vivo in an aging tumor microenvironment by rebuilding aged human skin. With this, in vitro migration and tumor invasion will be seen, evaluated by Matrigel Boyden chamber, 3D spheroid and skin reconstructions; skin reconstructions will be used to observe the effects of TEAD inhibitor treatment, the effects of young versus old fibroblasts will be compared and we will compare glycated (aged) versus normal collagen and we will verify the effects of TEAD inhibitor treatment in animals with resistant melanoma. Thus, this dataset may show whether inhibition of TEADi will improve the efficacy of BRAFi/MEKi in BRAF-mutated melanoma and whether it may indicate new options for the therapeutic development of melanoma. (AU)