Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors.

Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I-IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling >4,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab

Oncology Activity

The development of therapeutics to treat cancer is conceptually more difficult than for nonlife-threatening diseases for several reasons, including its complex pathophysiological nature, the molecular individuality of each tumor, and the robustness and predictability of preclinical models toward determining efficacy and safety. A major limitation to development of a “blockbuster” therapeutic strategy is the infinite combination of cellular and molecular perturbations and associated heterogeneity of causative genetic factors driving disease progression. Although challenging, the diversity of drug targets, coupled with the lethality of the disease, has encouraged studies of a vast array of approaches and opportunities for disease treatment over the years