2024 World Conference on Lung Cancer (WCLC) - ePosters-EP.12C.02 5-Azacytidine DegradedKRAS By Recruiting E3 Ubiquitin Ligase UBE3C

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The study investigates the potential of 5-Azacytidine in targeting KRAS proteins, known for their role in promoting tumorigenesis, invasion, drug resistance, and poor prognosis. Both wild-type and mutant forms of KRAS contribute to these challenges in cancer treatment. Developing agents that can degrade KRAS may provide new therapeutic avenues for targeting tumors and mitigating chemotherapy resistance.<br /><br />The research builds upon previous findings that 5-Azacytidine is capable of degrading KRAS proteins. This degradation process is facilitated by the recruitment of the E3 ubiquitin ligase UBE3C. When 5-Azacytidine was used, it enhanced the ubiquitination of KRAS, leading to its degradation through the ubiquitin-proteasome system. The degradation of KRAS by 5-Azacytidine is both time- and concentration-dependent, suggesting precise control over the process.<br /><br />Furthermore, the study demonstrated that inhibiting the proteasome with MG132 protected KRAS from degradation, confirming the involvement of the ubiquitin-proteasome pathway. Through immunoprecipitation and protein profiling, the interaction between KRAS and UBE3C was confirmed.<br /><br />The research proposes that 5-Azacytidine acts as a "molecular glue," facilitating the binding of KRAS to UBE3C, thus promoting KRAS degradation. As an extension of this study, the researchers aim to design and optimize new molecular glue compounds based on the scaffold of 5-Azacytidine. These compounds could act as potent degradation agents specifically targeting KRAS proteins.<br /><br />The insights from this study provide a foundation for developing novel strategies to overcome drug resistance in cancers with KRAS mutations, potentially improving outcomes for patients where traditional KRAS-targeted therapies are ineffective.

Asset Subtitle

HUA LIU

Meta Tag

Speaker HUA LIU

Topic Metastatic Non-small Cell Lung Cancer – Targeted Therapy

Keywords

5-Azacytidine

KRAS proteins

tumorigenesis

drug resistance

E3 ubiquitin ligase UBE3C

ubiquitin-proteasome system

molecular glue

cancer treatment

chemotherapy resistance

KRAS degradation