# Contextual Invertible World Models: A Neuro-Symbolic Agentic Framework for Colorectal Cancer Drug Response

arXiv: https://arxiv.org/abs/2603.02274 · HTML: https://mlsanity.com/paper/2603.02274/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Medical and surgical world models, one of 11 directions in World models.
- Builds on 1 of its 14 references that are in the map.
- First posted on arXiv 1 Mar 2026.

## Placed in

- World models / [Medical and surgical world models](https://mlsanity.com/wm/medical-and-surgical-world-models/)
- LLM agents and tool use / [Medical and scientific domain agents](https://mlsanity.com/agents/medical-and-scientific-domain-agents/)

## Builds on (most cited first, 1 of 1)

- [Deep Learning for Medical Image Analysis](https://mlsanity.com/paper/1708.08987/) (2017)

## Abstract (arXiv)

Precision oncology is currently limited by the small-N, large-P paradox, where high-dimensional genomic data is abundant but pharmacological response samples are sparse. While deep learning achieves predictive accuracy, it frequently fails to provide the mechanistic clarity required for clinical adoption. We present the Contextual Invertible World Model (CIWM), a Neuro-Symbolic Agentic Framework that bridges this gap by integrating a quantitative machine learning emulator with a Large Language Model reasoning layer. Utilising a stringently curated, high-fidelity data engineering pipeline on the Sanger GDSC dataset (( N=83 )), we isolate true biological signals from in vitro artifacts to establish a rigorous baseline predictive correlation for complex transcriptomics (( r=0.268 )). Through Inverse Reasoning, we perform in silico CRISPR perturbations across the colorectal landscape. The framework autonomously overturns classical mechanistic assumptions, identifying a hierarchical dominance of mutant KRAS over the APC/Wnt-axis in driving 5-fluorouracil resistance (( Delta=-0.0469 )) via a "KRAS Shield" mapped to MAPK/PI3K networks. Furthermore, the agentic layer identified a "PIK3CA Paradox", revealing that repairing PIK3CA inadvertently increases chemoresistance (( Delta=+0.0085 )) by triggering a compensatory feedback loop that hyperactivates the dominant MAPK survival pathway.