# PTEN-Loss Pan-Cancer Dependency Atlas — Findings

## Verdict: PASS (3/5 success criteria met, 1 partial, 1 not met due to power)

## Core Discovery: PI3Kβ Isoform Switch

Convergent evidence from CRISPR dependencies and PRISM drug sensitivity confirms that PTEN-null cells undergo a p110α→p110β isoform switch:
- **PIK3CB (p110β) ROBUST dependency**: Breast d=-2.23, Skin d=-1.50
- **PIK3CA (p110α) INVERSE dependency**: PTEN-lost are LESS dependent (Breast d=+0.95)
- **Inavolisib (PI3Kα inhibitor) INVERSE drug sensitivity**: PTEN-lost LESS sensitive (d=+0.44 pan-cancer)
- **Afuresertib (AKT inhibitor) PTEN-selective**: Uterus d=-1.97, Ovary d=-1.68, pan-cancer d=-0.73

This supports PI3Kβ-selective therapy (AZD8186, GSK2636771, GT220) as the rational strategy for PTEN-lost cancers.

## Key Numbers

| Cancer Type | PIK3CB d | PIK3CB FDR | Afuresertib d | Est. US Patients/yr |
|---|---|---|---|---|
| Breast | -2.229 | 3.6e-4 | -0.449 | ~18,643 |
| Skin/Melanoma | -1.497 | 2.2e-3 | -0.992 | ~12,076 |
| Uterus | +0.382 | NS | -1.970 | ~44,122 |
| Ovary | +0.172 | NS | -1.679 | ~1,180 |
| CNS/Brain | -0.323 | NS | -0.412 | ~5,040 |
| Prostate | — | insufficient lines | — | ~57,660 |

## Trial Gaps

14 cancer types with PTEN-loss populations lack targeted trials. Largest unmet needs: melanoma (~12K pts, 12% PTEN loss), bladder (~8.3K pts, 10%), bowel (~10.7K pts, 7%).

## Limitations

- Genome-wide screen underpowered (0 novel non-PI3K hits at FDR<0.05)
- Capivasertib and PI3Kβ-selective drugs absent from PRISM 24Q2
- Prostate cancer underrepresented in DepMap (3 lines)
- Combination drug candidates have unresolved BRD identifiers