Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer
Martina Troiani, Manuel Colucci, Mariantonietta D’Ambrosio, Ilaria Guccini, Emiliano Pasquini, Angelica Varesi, Aurora Valdata, Simone Mosole, Ajinkya Revandkar, Giuseppe Attanasio, Andrea Rinaldi, Anna Maria Rinaldi, Marco Bolis, Pietro E. Cippà, Andrea Alimonti
Abstract
Cells subjected to treatment with anti-cancer therapies can evade apoptosis through cellular senescence. Persistent senescent tumor cells remain metabolically active, possess a secretory phenotype, and can promote tumor proliferation and metastatic dissemination. Removal of senescent tumor cells (senolytic therapy) has therefore emerged as a promising therapeutic strategy. Here, using single-cell RNA-sequencing, we find that senescent tumor cells rely on the anti-apoptotic gene Mcl-1 for their survival. Mcl-1 is upregulated in senescent tumor cells, including cells expressing low levels of Bcl-2, an established target for senolytic therapy. While treatment with the Bcl-2 inhibitor Navitoclax results in the reduction of metastases in tumor bearing mice, treatment with the Mcl-1 inhibitor S63845 leads to complete elimination of senescent tumor cells and metastases. These findings provide insights on the mechanism by which senescent tumor cells survive and reveal a vulnerability that can be exploited for cancer therapy.