Research Focus

Research Focus

The RAS GTPase superfamily serves as a central regulatory node coordinating diverse cellular signaling pathways. Somatic mutations in RAS genes are among the most frequent in human cancer, and the development of allele-specific and pan-RAS inhibitors has reshaped the therapeutic landscape. However, the efficacy of these agents is often constrained by intrinsic and acquired resistance. Understanding the molecular basis of this resistance is essential for identifying predictive biomarkers and for developing more durable, mechanism-guided therapeutic strategies.

Therapeutic exploitation of the RAS degradation pathway

Our research has revealed that resistance to RAS inhibition is tightly linked to dysregulated RAS proteostasis. The dosage of RAS proteins determines both the sensitivity and the outcome of therapeutic interventions. Notably, RAS inhibitors paradoxically increase RAS protein expression, thereby attenuating their own efficacy. Notably, treatment with RAS inhibitors increases RAS protein levels, thereby attenuating their own therapeutic efficacy.

Our studies identified LZTR1, a Kelch-domain adaptor of the CUL3 ubiquitin ligase complex, as a key regulator of RAS protein stability. These discoveries established LZTR1 as a central node in RAS proteostasis and revealed its role in mediating resistance to RAS inhibitors. 

Building on this discovery, we are now developing strategies that exploit the endogenous RAS degradation machinery as a therapeutic avenue. One major line of investigation focuses on decoding the structural and regulatory principles of LZTR1-mediated RAS degradation to enable the rational design of degrader-based therapies. In parallel, we are identifying small-molecule molecular glues that stabilize the interaction between LZTR1 and RAS, thereby promoting selective RAS degradation. Together, these efforts aim to transform fundamental insights into clinically actionable strategies to overcome resistance in RAS-driven cancers.

RAS degradation and tumor immunogenicity

Emerging evidence from our immunopeptidomic analyses suggests that RAS degradation also has profound effects on antigen processing and presentation. We found that RAS degraders remodel the immunopeptidome of pancreatic cancer cells, potentially enhancing tumor immunogenicity through ER-stress–induced neoepitope generation. Ongoing work integrates lipidomics, translatome profiling, and T-cell activation assays to define the immunological consequences of RAS degradation and to explore its potential synergy with immunotherapy.

Long-Term Vision

We are extending our concept of targeted degradation beyond RAS by developing Kelch-based PROTAC platforms. The Kelch domain family, comprising over sixty human substrate adaptors, offers a powerful yet underexplored toolkit for selective protein degradation. We aim to enable the rational design of next-generation, tissue-specific PROTACs. Together, these programs will provide a foundation for precision oncology based on targeted proteolysis.