Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer

• DOI: 10.1038/s41467-022-29824-1
• Publication Date: 2022-04-21T10:03:06Z
• Authors: Martina Troiani; Manuel Colucci; Mariantonietta D’...; Ilaria Guccini; Emiliano Pasquini; Angelica Varesi; Aurora Valdata; Simone Mosole; Ajinkya Revandkar; Giuseppe Attanasio; Andrea Rinaldi; Anna Rinaldi; Marco Bolis; Pietro Cippà; Andrea Alimonti
• Keywords: 0301 basic medicine; Science; Q; Antineoplastic Agents; Apoptosis; Article; 3. Good health; Animals; Antineoplastic Agents/pharmacology; Antineoplastic Agents/therapeutic use; Apoptosis/genetics; Cellular Senescence/genetics; Mice; Neoplasms/drug therapy; Neoplasms/genetics; Proto-Oncogene Proteins c-bcl-2/genetics; Proto-Oncogene Proteins c-bcl-2/metabolism; Transcriptome; Mice; 03 medical and health sciences; Proto-Oncogene Proteins c-bcl-2; Neoplasms; Animals; Animals; Apoptosis; Cellular Senescence; Mice; Proto-Oncogene Proteins c-bcl-2; Transcriptome; Antineoplastic Agents; Neoplasms; Transcriptome; Cellular Senescence

AbstractCells 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.