2. Academic Validation
  3. The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy

The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy

  • Signal Transduct Target Ther. 2025 Mar 21;10(1):91. doi: 10.1038/s41392-025-02176-0.
Meike Vogler 1 2 3,  Yannick Braun 4 5,  Victoria M Smith 6,  Mike-Andrew Westhoff 7,  Raquel S Pereira 4,  Nadja M Pieper 4,  Marius Anders 4,  Manon Callens 8,  Tim Vervliet 8,  Maha Abbas 9,  Salvador Macip 6 9 10 11,  Ralf Schmid 12 13,  Geert Bultynck 8,  Martin Js Dyer 6
Affiliations

Affiliations

  • 1 Goethe University Frankfurt, Institute for Experimental Pediatric Hematology and Oncology, Frankfurt am Main, Germany. m.vogler@kinderkrebsstiftung-frankfurt.de.
  • 2 German Cancer Consortium (DKTK) partner site Frankfurt/Mainz, a partnership between DKFZ and University Hospital Frankfurt, Frankfurt am Main, Germany. m.vogler@kinderkrebsstiftung-frankfurt.de.
  • 3 University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany. m.vogler@kinderkrebsstiftung-frankfurt.de.
  • 4 Goethe University Frankfurt, Institute for Experimental Pediatric Hematology and Oncology, Frankfurt am Main, Germany.
  • 5 Department of Pediatric Surgery, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany.
  • 6 The Ernest and Helen Scott Haematological Research Institute, Leicester Cancer Research Centre, University of Leicester, Leicester, UK.
  • 7 Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
  • 8 KU Leuven, Lab. Molecular & Cellular Signaling, Dep. Cellular & Molecular Medicine, and Leuven Kankerinstituut (LKI), Leuven, Belgium.
  • 9 Mechanisms of Cancer and Ageing Laboratory, Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.
  • 10 Josep Carreras Leukaemia Research Institute, Badalona, Spain.
  • 11 FoodLab, Faculty of Health Sciences, Universitat Oberta de Catalunya, Barcelona, Spain.
  • 12 Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.
  • 13 Institute for Structural and Chemical Biology, University of Leicester, Leicester, UK.
PMID: 40113751 DOI: 10.1038/s41392-025-02176-0
Abstract

The B cell lymphoma 2 (BCL2) protein family critically controls Apoptosis by regulating the release of cytochrome c from mitochondria. In this cutting-edge review, we summarize the basic biology regulating the BCL2 family including canonical and non-canonical functions, and highlight milestones from basic research to clinical applications in Cancer and Other pathophysiological conditions. We review laboratory and clinical development of BH3-mimetics as well as more recent approaches including proteolysis targeting chimeras (PROTACs), antibody-drug conjugates (ADCs) and tools targeting the BH4 domain of BCL2. The first BCL2-selective BH3-mimetic, venetoclax, showed remarkable efficacy with manageable toxicities and has transformed the treatment of several hematologic malignancies. Following its success, several chemically similar BCL2 inhibitors such as sonrotoclax and lisaftoclax are currently under clinical evaluation, alone and in combination. Genetic analysis highlights the importance of BCL-XL and MCL1 across different Cancer types and the possible utility of BH3-mimetics targeting these proteins. However, the development of BH3-mimetics targeting BCL-XL or MCL1 has been more challenging, with on-target toxicities including thrombocytopenia for BCL-XL and cardiac toxicities for MCL1 inhibitors precluding clinical development. Tumor-specific BCL-XL or MCL1 inhibition may be achieved by novel targeting approaches using PROTACs or selective drug delivery strategies and would be transformational in many subtypes of malignancy. Taken together, we envision that the targeting of BCL2 proteins, while already a success story of translational research, may in the foreseeable future have broader clinical applicability and improve the treatment of multiple diseases.

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