# Impact of treatment history on drug resistance of metastatic colorectal cancer organoids

## TL;DR

This study shows that prior chemotherapy in colorectal cancer patients leads to genetic changes and drug resistance in tumor organoids, with different drugs causing distinct resistance mechanisms.

## Contribution

The study reveals how chemotherapy history alters organoid resistance mechanisms, including drug-specific genomic and phenotypic changes.

## Key findings

- PDOs from pretreated patients show increased mutations and distinct chemo-related signatures
- Oxaliplatin resistance is maintained in PDOs through tumor cell-intrinsic properties
- Deep deletions at CFS are linked to irinotecan resistance in PDOs from pretreated patients

## Abstract

The treatment of metastatic colorectal cancer (mCRC) is impeded by drug resistance. We investigated how prior chemotherapy affects tumor genotype, phenotype, and resistance mechanisms by comparing 35 patient-derived metastatic organoids (PDOs) from pretreated and chemonaive patients with mCRC. Combining PDO drug sensitivity assessments with RNA and whole genome sequencing, we found PDOs from pretreated patients exhibited higher mutational load and more structural variants. Chemotherapy-related mutational signatures correlated with previous exposure. PDOs from oxaliplatin-resistant patients maintained this resistance, showing the upregulation of ZNF300, TGM2, and Hedgehog pathway enrichment. Acquired resistance to 5-FU and irinotecan was only partially captured, with irinotecan resistance linked to specific mutational signatures and deep deletions in common fragile sites, associated with distinct gene expression profiles. Our findings reveal that PDOs capture chemotherapy-induced genomic and phenotypic changes differently depending on the drug, suggesting varied mechanisms of acquired resistance involving both tumor cell-intrinsic properties and dynamic tumor cell states.

•PDOs from pretreated patients show increased mutations and distinct chemo-related signatures•Oxaliplatin resistance is maintained in PDOs through tumor cell-intrinsic properties•Deep deletions at CFS are linked to irinotecan resistance in PDOs from pretreated patients•Gene expression patterns reveal distinct mechanisms for acquired vs. primary chemo-resistance

PDOs from pretreated patients show increased mutations and distinct chemo-related signatures

Oxaliplatin resistance is maintained in PDOs through tumor cell-intrinsic properties

Deep deletions at CFS are linked to irinotecan resistance in PDOs from pretreated patients

Gene expression patterns reveal distinct mechanisms for acquired vs. primary chemo-resistance

Health sciences; Medicine; Medical specialty; Internal medicine; Oncology; Biological sciences; Cancer