A09
Discovery and targeting of ubiquitin-dependent synthetic vulnerabilities in NSCLC
Project Summary
The ubiquitin-proteasome system (UPS) has recently gained increasing attention for cancer drug development. However, targeting the UPS is limited by functional redundancies and degeneracies within the UPS. Building on new genomic technologies, methods, and model systems developed by us, we propose to address this issue by systematically mapping genetic interactions in KRAS-driven non-small cell lung cancer (NSCLC). We will exploit high-throughput CRISPR/CasRx screening to probe millions of genetic target combinations affecting cellular fitness or cell identity changes. We aim to (i) identify synthetic dependencies within the UPS for the design of combinatorial therapies, (ii) map determinants of epithelial to mesenchymal plasticity and develop strategies to target plasticity-related evolution of chemotherapy resistance, (iii) explore mechanisms and perform preclinical genetic validation of new targets/target combinations, (iv) deconvolute their context-dependencies and initiate exploration of their druggability as a basis for drug development in subsequent funding periods. We describe unpublished proof-of-concept data for the proposed screens, which have already discovered first candidate UPS components for downstream mechanistic and therapeutic exploration. Collectively, these studies will unravel landscapes of co-dependencies and drug synergies at unprecedented scale and resolution.
