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BCL-xL dependency in chromophobe renal cell carcinoma

Cancer Gene Therapy volume 32, pages 1133–1143 (2025)Cite this article

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Abstract

Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of kidney cancer, with limited therapeutic options. Using BH3 profiling to screen ChRCC-derived cell lines, we discovered that BH3 peptides targeting BCL-xL promote apoptosis in ChRCC. Downregulation of BCL2L1 is sufficient to induce apoptosis in ChRCC-derived cells, consistent with our screening results. BCL2L1, encoding BCL-xL, is fourfold upregulated in ChRCC compared to normal kidney and has the second highest expression in The Cancer Genome Atlas. BCL2L1 downregulation enhances MCL-1 expression, suggesting a possible compensatory role for MCL-1. Based on these results, we evaluated two BH3 mimetics, A-1331852 (targeting BCL-xL) and S63845 (targeting MCL-1). Their combination resulted in 80% cell death. DT2216, a proteolysis-targeting chimera (PROTAC) that targets BCL-xL for degradation, induced cleaved PARP and caspase 3, indicators of apoptosis. ChRCC cells are known to be highly sensitive to ferroptosis. We combined A-1331852 and S63845 with IKE or RSL3 (ferroptosis-inducing drugs). BCL-xL and MCL-1 inhibition enhanced the susceptibility to ferroptosis, suggesting a link between apoptosis and ferroptosis in ChRCC. These data indicate that BCL-xL maintains ChRCC cell survival by suppressing apoptosis. The BCL-xL-specific PROTAC DT2216, currently in clinical trials, may provide an opportunity for ChRCC therapy.

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Fig. 1: ChRCC cell lines are unprimed for apoptosis and dependent on BCL-xL for survival.
Fig. 2: Genetic knockdown of BCL2L1 (encoding BCL-xL) leads to increased apoptotic cell death.
Fig. 3: MCL-1 inhibition enhances the effect of BCL-xL inhibition on cell death in ChRCC.
Fig. 4: BCL-xL degradation by PROTACs induces apoptotic cell death in ChRCC.
Fig. 5: BH3 mimetics sensitize ChRCC to ferroptosis.

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All data generated or analyzed during this study are included in this published article, and/or SI Appendix.

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Acknowledgements

This study was supported in part by the Tuttle Family Fund and a gift from Gigi Cohen and Michael Levin.

Author information

Authors and Affiliations

  1. Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Nadine Mahmoud, Wafaa Bzeih, Damir Khabibullin, Michel Alchoueiry, Steven Safi, Joelle Chami, Tiegang Han, Samer Salem, Carmen Priolo & Elizabeth P. Henske

  2. John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Xingping Qin & Kristopher A. Sarosiek

  3. Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, MA, USA

    Xingping Qin & Kristopher A. Sarosiek

  4. Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Xingping Qin & Kristopher A. Sarosiek

  5. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

    Abhishek A. Chakraborty

  6. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Kristopher A. Sarosiek

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  1. Nadine Mahmoud
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Contributions

NM, XQ, SS, DK, CP, AAC, KAS, and EPH designed research; NM, XQ, SS, DK, WB, SS, JC, and MA performed research; XQ, AAC, and KAS contributed new reagents/analytic tools; NM, XQ, TH, KAS, and EPH, MA, and WB analyzed data; and NM and EPH wrote the paper; XQ, DK, CP, AAC, and KAS provided feedback on the paper.

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Correspondence to Elizabeth P. Henske.

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All methods were performed in accordance with relevant guidelines and regulations. This in vitro study did not involve human participants, animals, or identifiable human images. Therefore, ethical approval from an ethics committee and informed consent were not required.

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Mahmoud, N., Qin, X., Bzeih, W. et al. BCL-xL dependency in chromophobe renal cell carcinoma. Cancer Gene Ther 32, 1133–1143 (2025). https://doi.org/10.1038/s41417-025-00953-1

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