# Training distribution determines the ceiling of drug-blind cancer sensitivity prediction

arXiv: https://arxiv.org/abs/2605.20885 · HTML: https://mlsanity.com/paper/2605.20885/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 2 of its 23 references that are in the map.
- First posted on arXiv 20 May 2026.

## Builds on (most cited first, 2 of 2)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [ChemBERTa: Large-Scale Self-Supervised Pretraining for Molecular Property Prediction](https://mlsanity.com/paper/2010.09885/) (2020)

## Abstract (arXiv)

Precision oncology requires predicting which drugs will suppress a specific tumor from its molecular profile, but drug-blind sensitivity prediction has plateaued despite increasingly complex drug representations. Here we show that this stagnation reflects a metric artifact rather than a representational bottleneck. The standard benchmark, global Pearson r, is dominated by between-drug potency differences that a trivial drug-mean predictor captures without any cell-specific learning. Per-drug Pearson r, which isolates within-drug cell ranking, reveals that no drug encoding improves over cell-only features across four independent datasets. A controlled experiment channeling mechanism-of-action identity as either a drug feature or a training-distribution constraint identifies the cause. Supplying MoA as a feature yields negligible benefit, whereas using it to stratify training raises per-drug r substantially for targeted kinase inhibitors, because pan-cancer co-training suppresses pathway-specific sensitivity signals. Mechanism-stratified training and response matching from pilot observations provide two deployable strategies that together recover the principal sources of predictive gain in drug-blind sensitivity prediction.