Purpose: Advanced/metastatic forms of clear-cell renal cell carcinomas (ccRCC) have limited therapeutic options. Genome-wide genetic screens have identified cellular dependencies in many cancers. Using the Broad Institute/Novartis combined short hairpin RNA (shRNA) dataset, and cross-validation with the CRISPR/Cas9 DepMap (21Q3) dataset, we sought therapeutically actionable dependencies in kidney lineage cancers.
Experimental Design: We identified preferential genetic dependencies in kidney cancer cells versus other lineages. BCL2L1, which encodes the BCL-XL antiapoptotic protein, scored as the top actionable dependency. We validated this finding using genetic and pharmacologic tools in a panel of ccRCC cell lines. Select BCL-XL-dependent (versus independent) cell lines were then transcriptionally profiled to identify biomarkers and mechanistic drivers of BCL-XL dependence. Cell-based studies (in vitro and in vivo) and clinical validations were used to address physiologic relevance.
Results: Inactivation of BCL-XL, but not BCL-2, led to fitness defects in renal cancer cells, and sensitized them to chemotherapeutics. Transcriptomic profiling identified a "BCL-XL dependency" signature, including an elevated mesenchymal gene signature. A mesenchymal state was both necessary and sufficient to confer increased BCL-XL dependence. The "BCL-XL dependency" signature was observed in approximately 30% of human ccRCCs, which were also associated with worse clinical outcomes. Finally, an orally bioavailable BCL-XL inhibitor, A-1331852, showed antitumor efficacy in vivo.
Conclusions: Our studies uncovered an unexpected link between cell state and BCL-XL dependence in ccRCC. Therapeutic agents that specifically target BCL-XL are available. Our work justifies testing the utility of BCL-XL blockade to target, likely, a clinically aggressive subset of human kidney cancers. See related commentary by Wang et al., p. 4600.
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http://dx.doi.org/10.1158/1078-0432.CCR-22-0669 | DOI Listing |
Cell Death Differ
December 2024
Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
Cellular senescence is a stress response that cells can employ to resist cell death. Senescent cells rely on anti-apoptotic signaling for their survival, which can be targeted by senolytic agents, like the BCL-XL, BCL-2, BCL-W inhibitor ABT-263. However, the response to ABT-263 of senescent cancer cells ranges from highly sensitive to refractory.
View Article and Find Full Text PDFCancer Cell Int
December 2024
Division of Fusion Radiology Research, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Korea.
Background: Paclitaxel resistance and recurrence are major obstacles in ovarian cancer, which is the leading cause of death among gynecologic cancers. During cancer cell progression, cyclin-dependent kinase 1 (CDK1) drives cells through the G2 phase and into mitosis. In this study, we demonstrated that CDK1 played a crucial role in switching paclitaxel-resistant ovarian cancer cells from mitotic arrest to apoptosis following combined treatment with paclitaxel and duloxetine, an antidepressant known as a serotonin-norepinephrine reuptake inhibitor (SNRI).
View Article and Find Full Text PDFTransl Vis Sci Technol
December 2024
Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Purpose: To investigate the toxicity of terpinen-4-ol (T4O) on primary cultured human corneal epithelial cells (HCECs).
Methods: HCECs were exposed to various concentrations (0%-0.1%) of T4O for 15 minutes to 72 hours.
Biomedicines
October 2024
Department of Biomedical Engineering, Dongguk University, Goyang-si 10326, Republic of Korea.
Until now, many researchers have conducted evaluations on hippocampi for analyses of cognitive dysfunction models using scopolamine. However, depending on the purposes of these analyses, there are differences in the experimental results for the hippocampi and cortexes. Therefore, this study intends to compare various analyses of cognitive dysfunction after scopolamine administration with each other in hippocampi and cortexes.
View Article and Find Full Text PDFActa Pharmacol Sin
November 2024
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
HER2-positive gastric cancer has a poor prognosis, with a high incidence of drug resistance and a lack of effective treatments for drug-resistant patients. The exploration of the mechanism of resistance to HER2-targeted therapy in HER2-positive gastric cancer and the identification of effective strategies to reverse it are urgently needed. In this study, we found that HER2-targeted agents upregulated the expression of GSDME and that the overexpression of GSDME attenuated the sensitivity of HER2-targeted agents.
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