A molecularly annotated platform of patient-derived xenografts ('xenopatients') identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer
A partir d'une cohorte de xénogreffes fabriquées avec 85 échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal métastatique, cette étude suggère que, dans certains cas, l'inhibition de HER2 pourrait être efficace chez les patients dont les tumeurs ont développé une résistance au cetuximab
Only a fraction of patients with metastatic colorectal cancer (mCRC) have clinical benefit from therapy with anti-EGFR antibodies, which calls for the identification of novel biomarkers for better personalized medicine. We produced large xenograft cohorts from 85 patient-derived, genetically characterized mCRC samples ('xenopatients') to discover novel determinants of therapeutic response and new druggable driver oncoproteins. Serially passaged tumors retained the morphological and genomic features of their original counterparts. A validation trial confirmed the robustness of this approach: xenopatients responded to the anti-EGFR antibody cetuximab with rates and extents analogous to those observed in the clinic and could be prospectively stratified as responders or non-responders based on several predictive biomarkers. Genotype-response correlations indicated HER2 amplification in 2.7% of unselected tumors and in 36% of cetuximab-resistant, KRAS/NRAS/BRAF/PIK3CA wild-type cases. Importantly, HER2 amplification was also enriched (13.6%) in clinically nonresponsive KRAS wild-type patients. A proof-of-concept, multi-arm study in HER2-amplified xenopatients revealed that combined inhibition of HER2 and EGFR induced overt, long-lasting tumor regression. Our results suggest promising therapeutic opportunities in cetuximab-resistant mCRC patients, whose medical treatment in the chemorefractory setting remains an unmet clinical need.