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Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer
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Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer
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Journal Article
Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer
2022
Overview
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.
Cell senescence remains a barrier to tumor elimination in many cancers. Here, the authors use single cell RNA-seq to identify a role for Mcl-1 in senescent cell survival, and show that Mcl-1 inhibition may be an effective therapeutic strategy.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 45/77
/ 49/91
/ 82/1
/ 82/51
/ Animals
/ Antineoplastic Agents - pharmacology
/ Antineoplastic Agents - therapeutic use
/ Cancer
/ Cellular Senescence - genetics
/ Humanities and Social Sciences
/ Mice
/ Proto-Oncogene Proteins c-bcl-2 - genetics
/ Proto-Oncogene Proteins c-bcl-2 - metabolism
/ RNA
/ Science
/ Survival
/ Therapy
/ Tumors
