## Executive Summary

WRN helicase is a ROBUST synthetic lethal target in MSI-H cancers. Using DepMap 25Q3, this atlas classified 2,119 cell lines by MSI status (70 MSI-H, 2,049 MSS) and systematically ranked all MSI-H cancer types by WRN dependency.

## Key Findings

1. **WRN-MSI SL confirmed ROBUST** in Bowel (d=-2.844, FDR=1.1e-6), Uterus (d=-1.086, FDR=0.050), and pan-cancer pooled (d=-2.833, FDR=1.4e-11). BLM/RECQL controls NOT_SIGNIFICANT.

2. **TP53-GOF weakens WRN dependency** (TP53-WT=-1.354, GOF-hotspot=-0.505, d=-0.556, p=0.026). Potential resistance biomarker consistent with p53/PUMA-dependent mechanism.

3. **Novel MSI-H dependencies**: PELO (d=-2.876, ribosome rescue), RPL22L1 (d=-2.602, paralog essentiality), DHX9 (d=-1.682, R-loop resolution). 186 gained + 98 lost MSI-H dependencies from 53,793 tests.

4. **DNA-PKi convergence**: AZD-7648 MSI-H selective (d=-0.526, FDR=0.018) from PRISM, independently converging with resistance preprint identifying DNA-PK as combination partner.

5. **~61,854 US MSI-H patients/yr**. Top: COADREAD (~23,532), UCEC (~20,974), STAD (~5,297). 13 MSI-H tumor types lack WRN trial enrollment.

6. **Three WRN inhibitors (VVD-214, HRO-761, NDI-219216) with divergent resistance profiles** enable rational sequential therapy. Compound-specific resistance mutations spare sensitivity to other compounds.

7. **Clinical landscape concordance (new)**: VVD-214 Phase 1 shows 4 PRs in 32 evaluable MSI-H pts (ORR ~12.5%), consistent with WRN as a tractable target under sub-optimal Phase 1 dosing. No correlation between pembrolizumab ORR and WRN dependency across tumor types (UCEC: highest IO response 57.1% but weakest WRN d=-1.086), suggesting WRN inhibitors and IO are complementary. PAAD (pembro ORR 18.2%) represents the clearest unmet need. Key untested predictions — lineage-specific effect size variation, TP53 as response modifier, DNA-PKi combination — are high-priority translational hypotheses for current trials.