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Timm M. Reissig, Swetlana Ladigan-Badura, Anja Steinberg, Abdelouahid Maghnouj, Ting Li, Berlinda Verdoodt, Sven-Thorsten Liffers, Michael Pohl, Heiner Wolters, Christian Teschendorf, Richard Viebahn, Jakob Admard, Nicolas Casadei, Andrea Tannapfel, Wolff-Helmut Schmiegel, Stephan Hahn, Deepak Vangala

• Although approximately half of all metastatic colorectal cancers (mCRCs) harbour mutations in \(\it KRAS\) or \(\it NRAS\), hardly any progress has been made regarding targeted treatment for this group over the last few years. Here, we investigated the efficacy of vertical inhibition of the RAS-pathway by targeting epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase kinase (MEK) in patient-derived xenograft (PDX) tumours with primary \(\it KRAS\) mutation. In total, 19 different PDX models comprising 127 tumours were tested. Responses were evaluated according to baseline tumour volume changes and graded as partial response (PR; ≤ − 30%), stable disease (SD; between −30% and +20%) or progressive disease (PD; ≥ + 20%). Vertical inhibition with trametinib and cetuximab induced SD or PR in 74% of analysed models, compared to 24% by monotherapy with trametinib. In cases of PR by vertical inhibition (47%), responses were lasting (as long as day 137), with a low incidence of secondary resistance (SR). Molecular analyses revealed that primary and SR was driven by transcriptional reprogramming activating the RAS pathway in a substantial fraction of tumours. Together, these preclinical data strongly support the translation of this combination therapy into clinical trials for CRC patients.