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

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.

Single cell sequencing revealed the mechanism of CRYAB in glioma and its diagnostic and prognostic value

“…However, the effectiveness of surgery alone is often limited. Additional treatment options include radiation therapy and chemotherapy, although their outcomes are also unsatisfactory ( 49 ). Novel approaches such as targeted therapy and immunotherapy have emerged with the aim of interfering with specific signaling pathways in glioma cells or enhancing the immune system to suppress tumor growth.…”

Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies

“…Additionally, there are other proteins, such as the anti-apoptotic BCL-2 family member proteins, that mediate resistance mechanisms in medulloblastoma [ 34 ]. Members of the BCL-2 family such as BCL-XL and MCL-1 have been specifically highlighted for their chemoresistance properties in medulloblastoma, since anti-apoptosis is a key characteristic of cancer that is related to chemoresistance [ 34 , 47 ]. Furthermore, mutations of certain proteins are known to confer drug resistance in medulloblastoma as well; for example, SMO mutations resulting from use of the Hedgehog inhibitor GDC-0449 can disrupt the binding of drugs and induce drug resistance [ 48 ].…”

“…The NOTCH signaling pathway helps balance the ratio of cell proliferation to apoptosis [ 55 ]. A skewed balance in favor of proliferation over apoptosis that occurs with NOTCH dysregulation is undoubtedly connected to tumorigenesis and drug resistance, as inhibited apoptosis is associated with therapy resistance [ 47 ].…”