CDK2 as a therapeutic target in MYC-driven medulloblastoma

• Group 3 medulloblastoma (MB) is a malignant pediatric brain tumor that shows aberrant cell cycle activation, therapy resistance, and poor prognosis. Here, we identified that MYC expression and poor prognosis in Group 3 MB correlates with elevated levels of core cell cycle members CDK2 and cyclin A2, suggesting they would be promising targets for direct inhibition. Tumor cells in a novel transgenic MYC-driven MB mouse model further displayed increased p27 levels, decreased viability, and cell growth in vitro upon conditional CDK2 depletion using tamoxifen-induced recombination. Human Group 3 MB cells transduced with dominant-negative CDK2 mutants similarly exhibited decreased viability and increased p27 activation. As compared to controls, CDK2-depleted cells responded less to CDK2-specific inhibitors but were not more sensitive to BET inhibition or CDK4/6 inhibition as previously proposed. We finally used global transcriptional profiling and found that mTOR and B-Myb/ZMYM2 signaling pathways are compensating for CDK2 loss in Group 3MB cells. Our analysis suggests that specific inhibitors of these pathways could in combination with approved cell cycle inhibitors provide more efficient treatments for this severe childhood brain cancer.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

medulloblastoma

MYC

CDK2

mouse model

treatment

Oncology

Onkologi

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