A specific region on the RAS protein, called the Switch I/II pocket, can be bound by different types of drugs and proteins, suggesting it’s a reliable target for developing treatments against many RAS-driven cancers.
Evidence from Studies
No evidence studies found yet.
What Would Prove This
Per GRADE and EBM methodology, here is what ideal scientific evidence would look like to definitively prove or disprove this claim, ordered from strongest to weakest.
Whether targeting the Switch I/II pocket with any therapeutic modality consistently leads to clinical benefit across multiple RAS-mutant cancer types.
A systematic review and meta-analysis of all clinical trials and preclinical studies evaluating Switch I/II pocket inhibitors (biologics, small molecules) in RAS-mutant cancers, assessing target engagement, pathway suppression, and clinical outcomes.
Whether a Switch I/II pocket inhibitor improves survival compared to non-targeted therapy in patients with diverse RAS mutations.
A double-blind RCT of 350 patients with KRAS, HRAS, or NRAS-mutant cancers, randomized to a Switch I/II-targeting agent (e.g., JAM20 analog) or standard chemotherapy, with overall survival as primary endpoint and tumor RAS mutation subtype as stratification factor.
Whether tumors with high Switch I/II pocket accessibility predict response to inhibitors targeting this region.
A prospective cohort of 200 patients with RAS-mutant cancers treated with a Switch I/II inhibitor, using structural modeling of tumor RAS to quantify pocket accessibility and correlating with treatment response and survival.
Whether patients who respond to Switch I/II inhibitors have tumors with higher pocket conservation than non-responders.
A case-control study comparing 50 responders to a Switch I/II inhibitor with 100 non-responders, analyzing RAS mutation types and structural models of the Switch I/II pocket for conservation scores.
The frequency of RAS mutations that preserve the Switch I/II pocket structure across cancer types.
A cross-sectional analysis of 600 tumor samples from pancreatic, lung, and colorectal cancers, using structural bioinformatics to determine the proportion of KRAS, HRAS, and NRAS mutations that maintain an intact Switch I/II pocket.