# A molecularly annotated platform of patient-derived xenografts identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer

Source: https://onco.cc/key-papers/paper-bertotti-xenopatients-her2-cetuximab-resistant-colorectal-cancer-discov-2011/  
OnCo record `paper-bertotti-xenopatients-her2-cetuximab-resistant-colorectal-cancer-discov-2011` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Growing 85 patients' bowel cancers in mice and treating them like a clinical trial reproduced the pattern seen in people, and revealed that the tumours resisting cetuximab despite normal RAS often have extra copies of HER2.

## Summary

Large xenograft cohorts were produced from 85 patient-derived, genetically characterised metastatic colorectal cancer samples. Serially passaged tumours retained the morphological and genomic features of their originals, and a validation trial confirmed that they responded to cetuximab with rates and extents analogous to those seen in the clinic, and could be prospectively stratified as responders or non-responders using predictive biomarkers. Genotype-response correlations indicated HER2 amplification specifically in a subset of cetuximab-resistant, KRAS, NRAS, BRAF and PIK3CA wild-type cases, and HER2 amplification was also enriched among clinically non-responding KRAS wild-type patients. A proof-of-concept, multi-arm study in HER2-amplified xenopatients showed that combined inhibition of HER2 and EGFR induced overt, long-lasting tumour regression.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Cancer Discovery
- Year: 2011
- DOI: 10.1158/2159-8290.CD-11-0109
- Authors: Bertotti A, Migliardi G, Galimi F, et al.
- Findings: Patient-derived xenografts reproduced clinical cetuximab response rates and biomarker stratification.; HER2 amplification enriched in cetuximab-resistant, quadruple wild-type cases.; Dual HER2 and EGFR inhibition produced long-lasting regressions in HER2-amplified xenografts.
- What it means: It is where HER2-directed colorectal therapy came from: the xenopatient result led directly to HERACLES and therefore to every HER2 regimen now used in the disease.
- Caveats: Mouse models without an immune system.; Small numbers of HER2-amplified cases, as in patients.; The clinical benefit of dual blockade has been shorter-lived than the xenograft regressions suggested.

## Sources

- Bertotti et al., Cancer Discov 2011: xenopatients identify HER2 amplification in cetuximab-resistant colorectal cancer: https://doi.org/10.1158/2159-8290.CD-11-0109
- PubMed: https://pubmed.ncbi.nlm.nih.gov/22586653/

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- technologies: [Patient-derived organoids](https://onco.cc/technologies/organoids/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [HER2](https://onco.cc/targets/her2/), [KRAS](https://onco.cc/targets/kras/)
- drugs: [Cetuximab](https://onco.cc/drugs/cetuximab/), [Lapatinib](https://onco.cc/drugs/lapatinib/), [Trastuzumab](https://onco.cc/drugs/trastuzumab/)
- institutions: [Istituto di Candiolo IRCCS (FPO)](https://onco.cc/institutions/candiolo/)
- pathways: [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- terms: [Gene amplification and copy-number change](https://onco.cc/terms/gene-amplification/), [Wild-type (WT)](https://onco.cc/terms/wild-type/)
- journals: [Cancer Discovery](https://onco.cc/journals/cancer-discovery/)
- trials: [HERACLES](https://onco.cc/trials/heracles/)

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