Targeting the Non-Homologous End-Joining Pathway Sensitizes MDM2-Amplified Liposarcoma to Doxorubicin by Enhancing p53-Mediated Senescence - PubMed
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- #Senescence
- #Liposarcoma
- #p53
- Dedifferentiated liposarcoma (DDLPS) is characterized by MDM2 and CDK4 amplification, often showing resistance to conventional therapies like doxorubicin.
- CRISPR-Cas9 knockout screens identified genes related to G1/S transition (e.g., CDK2, CCNE1) and non-homologous end-joining (NHEJ; e.g., TDP2, PRKDC) as key to sensitizing DDLPS to palbociclib and doxorubicin.
- Inhibition of NHEJ pathway components (e.g., DNA-PKcs via peposertib) synergized with low-dose doxorubicin to induce p53-mediated senescence, which could be exploited therapeutically.
- Senescent cells triggered by this combination were susceptible to apoptosis via Bcl2 inhibitor navitoclax, suggesting a potential sequential treatment strategy.
- Despite MDM2 amplification, p53 activity was maintained in DDLPS, as supported by TCGA and DepMap data, enabling senescence-based therapeutic approaches.