{"entity":{"id":"paper-bertotti-xenopatients-her2-cetuximab-resistant-colorectal-cancer-discov-2011","kind":"paper","name":"A molecularly annotated platform of patient-derived xenografts identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer","aka":[],"tldr":"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.","asOf":"2026-09-24","links":[{"label":"Bertotti et al., Cancer Discov 2011: xenopatients identify HER2 amplification in cetuximab-resistant colorectal cancer","url":"https://doi.org/10.1158/2159-8290.CD-11-0109"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22586653/"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":["organoids"],"targets":["her2","egfr","kras"],"drugs":["cetuximab","trastuzumab","lapatinib"],"companies":[],"institutions":["candiolo"],"pathways":["rtk-activation","ras-mapk"],"terms":["wild-type","gene-amplification"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["cancer-discovery"],"dependsOn":[],"notes":[],"journal":"Cancer Discovery","year":2011,"doi":"10.1158/2159-8290.CD-11-0109","pmid":"22586653","authors":"Bertotti A, Migliardi G, Galimi F, et al.","paperType":"translational","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."],"whatItMeans":"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."],"changedPractice":false,"participants":85},"route":"/key-papers/paper-bertotti-xenopatients-her2-cetuximab-resistant-colorectal-cancer-discov-2011/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"technology":[{"id":"organoids","kind":"technology","name":"Patient-derived organoids","route":"/technologies/organoids/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"drug":[{"id":"cetuximab","kind":"drug","name":"Cetuximab","route":"/drugs/cetuximab/"},{"id":"lapatinib","kind":"drug","name":"Lapatinib","route":"/drugs/lapatinib/"},{"id":"trastuzumab","kind":"drug","name":"Trastuzumab","route":"/drugs/trastuzumab/"}],"institution":[{"id":"candiolo","kind":"institution","name":"Istituto di Candiolo IRCCS (FPO)","route":"/institutions/candiolo/"}],"pathway":[{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"}],"term":[{"id":"gene-amplification","kind":"term","name":"Gene amplification and copy-number change","route":"/terms/gene-amplification/"},{"id":"wild-type","kind":"term","name":"Wild-type (WT)","route":"/terms/wild-type/"}],"journal":[{"id":"cancer-discovery","kind":"journal","name":"Cancer Discovery","route":"/journals/cancer-discovery/"}],"trial":[{"id":"heracles","kind":"trial","name":"HERACLES","route":"/trials/heracles/"}]}}