Abstract
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 precision 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.
Original language | English (US) |
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Article number | 111826 |
Journal | Cell Reports |
Volume | 41 |
Issue number | 12 |
DOIs | |
State | Published - Dec 20 2022 |
Externally published | Yes |
Keywords
- Aurora kinase
- BAX
- BCL-2
- BCL-xL
- CP: Cancer
- p21
- p53
- patient-derived organoids
- senescence
- senogenic
- senolytic
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology