## Key Findings

**CDK2 is a validated pan-cancer synthetic lethal target in RB1-loss cancers** (Cohen's d=-0.524, 95% CI [-0.683, -0.379], FDR=3.2e-9), confirmed across 493 RB1-deficient cell lines and 19 qualifying cancer types. CCNE1 co-amplification intensifies CDK2 dependency dramatically (double-hit d=-2.280), supporting convergent targeting with INX-315 (FDA Fast Track for CCNE1-amp ovarian cancer).

**Novel SAGA/ATAC chromatin complex dependencies** — TADA2A (d=-0.423), YEATS2 (d=-0.386), ZZZ3 (d=-0.385), CHD8 (d=-0.316) — emerged from the genome-wide screen, suggesting E2F-deregulated transcription creates dependency on chromatin remodeling. Hypothesis-generating.

**RB1-loss and CDKN2A-deletion landscapes are distinct:** 9 shared vs 30 RB1-unique vs 109 CDKN2A-unique dependencies. Upstream vs downstream pathway disruption yields different vulnerability profiles.

**CDK4/CDK6 negative controls validated:** dependency lost in RB1-null lines (CDK4 d=+0.36, CDK6 d=+0.64), confirming classifier accuracy.

**SCLC represents the largest addressable population** (~28,500 US pts/yr, ~95% RB1 loss) with no approved targeted therapies. CDK2 inhibitors could be first-in-class.

**PRISM drug validation limited** to trilaciclib only (CDK4/6i negative control, d=+0.678). CDK2 inhibitors too new for PRISM.

**INX-315 convergence:** Phase 1 data: 10% PR, 63% SD (31 pts). CCNE1-amp and RB1-loss converge on CDK2 dependency — INX-315 may cover both populations (~125,000 US RB1-loss pts/yr).