Targeting p53 for Melanoma Treatment: Counteracting Tumour Proliferation, Dissemination and Therapeutic Resistance

SIMPLE SUMMARY: Melanoma is a highly metastatic and therapy-resistant cancer and is therefore associated with low survival rates of patients. In melanoma, the inactivation of the wild-type form of the p53 tumour suppressor protein is a frequent event, mainly through interactions with MDM2 and MDMX. In this work, our recently disclosed p53-activating agent, SLMP53-2, displayed promising in vitro and in vivo antitumour activity, with particular impacts on melanoma migration and invasion. Moreover, SLMP53-2 (re)sensitized melanoma cells to clinically used chemotherapeutic agents, potentially overcoming the therapeutic resistance issue. As a whole, the p53 activator SLMP53-2 may represent a new therapeutic opportunity for melanoma, particularly in combination with MAPK pathway-targeting drugs. ABSTRACT: Melanoma is the deadliest form of skin cancer, primarily due to its high metastatic propensity and therapeutic resistance in advanced stages. The frequent inactivation of the p53 tumour suppressor protein in melanomagenesis may predict promising outcomes for p53 activators in melanoma therapy. Herein, we aimed to investigate the antitumor potential of the p53-activating agent SLMP53-2 against melanoma. Two- and three-dimensional cell cultures and xenograft mouse models were used to unveil the antitumor activity and the underlying molecular mechanism of SLMP53-2 in melanoma. SLMP53-2 inhibited the growth of human melanoma cells in a p53-dependent manner through induction of cell cycle arrest and apoptosis. Notably, SLMP53-2 induced p53 stabilization by disrupting the p53–MDM2 interaction, enhancing p53 transcriptional activity. It also promoted the expression of p53-regulated microRNAs (miRNAs), including miR-145 and miR-23a. Moreover, it displayed anti-invasive and antimigratory properties in melanoma cells by inhibiting the epithelial-to-mesenchymal transition (EMT), angiogenesis and extracellular lactate production. Importantly, SLMP53-2 did not induce resistance in melanoma cells. Additionally, it synergized with vemurafenib, dacarbazine and cisplatin, and resensitized vemurafenib-resistant cells. SLMP53-2 also exhibited antitumor activity in human melanoma xenograft mouse models by repressing cell proliferation and EMT while stimulating apoptosis. This work discloses the p53-activating agent SLMP53-2 which has promising therapeutic potential in advanced melanoma, either as a single agent or in combination therapy. By targeting p53, SLMP53-2 may counteract major features of melanoma aggressiveness.