BCL-xL inhibition potentiates cancer therapies by redirecting the outcome of p53 activation from senescence to apoptosis

Vijaya Bharti, Reese Watkins, Amrendra Kumar, Rebecca L. Shattuck-Brandt, Alexis Mossing, Arjun Mittra, Chengli Shen, Allan Tsung, Alexander E. Davies, Walter Hanel, John C. Reneau, Catherine Chung (+4 others)
2022 Cell Reports  
Cancer therapies trigger diverse cellular responses, ranging from apoptotic death to acquisition of persistent therapy-refractory states such as senescence. Tipping the balance toward apoptosis could improve treatment outcomes regardless of therapeutic agent or malignancy. We find that inhibition of the mitochondrial protein BCL-xL increases the propensity of cancer cells to die after treatment with a broad array of oncology drugs, including mitotic inhibitors and chemotherapy. Functional
more » ... ion oncology and omics analyses suggest that BCL-xL inhibition redirects the outcome of p53 transcriptional response from senescence to apoptosis, which likely occurs via caspase-dependent down-modulation of p21 and downstream cytostatic proteins. Consequently, addition of a BCL-2/xL inhibitor strongly improves melanoma response to the senescence-inducing drug targeting mitotic kinase Aurora kinase A (AURKA) in mice and patient-derived organoids. This study shows a crosstalk between the mitochondrial apoptotic pathway and cell cycle regulation that can be targeted to augment therapeutic efficacy in cancers with wild-type p53.
doi:10.1016/j.celrep.2022.111826 pmid:36543138 pmcid:PMC10030045 fatcat:af7p575g6nbujj42ijdywtwxdq