1. Academic Validation
  2. The identification of BCL-XL and MCL-1 as key anti-apoptotic proteins in medulloblastoma that mediate distinct roles in chemotherapy resistance

The identification of BCL-XL and MCL-1 as key anti-apoptotic proteins in medulloblastoma that mediate distinct roles in chemotherapy resistance

  • Cell Death Dis. 2023 Oct 28;14(10):705. doi: 10.1038/s41419-023-06231-y.
Marie-Claire Fitzgerald 1 2 Philip J O'Halloran 1 3 Sean A Kerrane 1 2 Triona Ní Chonghaile 1 Niamh M C Connolly 1 4 Brona M Murphy 5 6
Affiliations

Affiliations

  • 1 Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 31A York Street, Dublin, D02 YN77, Ireland.
  • 2 National Children's Research Centre at the Children's Health Ireland at Crumlin, Dublin, D12 N512, Ireland.
  • 3 Department of Neurosurgery, Queen Elizabeth Hospital, Birmingham, UK.
  • 4 Centre for Systems Medicine, Royal College of Surgeons in Ireland, 31A York Street, Dublin, D02 YN77, Ireland.
  • 5 Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 31A York Street, Dublin, D02 YN77, Ireland. bronamurphy@rcsi.com.
  • 6 National Children's Research Centre at the Children's Health Ireland at Crumlin, Dublin, D12 N512, Ireland. bronamurphy@rcsi.com.
Abstract

Medulloblastoma is the most common malignant paediatric brain tumour, representing 20% of all paediatric intercranial tumours. Current aggressive treatment protocols and the use of radiation therapy in particular are associated with high levels of toxicity and significant adverse effects, and long-term sequelae can be severe. Therefore, improving chemotherapy efficacy could reduce the current reliance on radiation therapy. Here, we demonstrated that systems-level analysis of basal Apoptosis protein expression and their signalling interactions can differentiate between medulloblastoma cell lines that undergo Apoptosis in response to chemotherapy, and those that do not. Combining computational predictions with experimental BH3 profiling, we identified a therapeutically-exploitable dependence of medulloblastoma cells on Bcl-xL, and experimentally validated that Bcl-xL targeting, and not targeting of Bcl-2 or Mcl-1, can potentiate cisplatin-induced cytotoxicity in medulloblastoma cell lines with low sensitivity to cisplatin treatment. Finally, we identified Mcl-1 as an anti-apoptotic mediator whose targeting is required for Bcl-xL inhibitor-induced Apoptosis. Collectively, our study identifies that Bcl-xL and Mcl-1 are the key anti-apoptotic proteins in medulloblastoma, which mediate distinct protective roles. While Bcl-xL has a first-line role in protecting cells from Apoptosis basally, Mcl-1 represents a second line of defence that compensates for Bcl-xL upon its inhibition. We provide rationale for the further evaluation of Bcl-xL and Mcl-1 inhibitors in the treatment of medulloblastoma, and together with current efforts to improve the cancer-specificity of Bcl-2 Family inhibitors, these novel treatment strategies have the potential to improve the future clinical management of medulloblastoma.

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