Lasting response by vertical inhibition with cetuximab and trametinib in \(\it KRAS\)-mutated colorectal cancer patient-derived xenografts

  • 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.

Download full text files

Export metadata

Additional Services

Share in Twitter Search Google Scholar
Author:Timm M. ReissigORCiDGND, Swetlana Ladigan-BaduraORCiDGND, Anja SteinbergGND, Abdelouahid MaghnoujGND, Ting LiGND, Berlinda VerdoodtGND, Sven-Thorsten LiffersGND, Michael PohlORCiDGND, Heiner WoltersORCiDGND, Christian TeschendorfGND, Richard ViebahnORCiDGND, Jakob AdmardGND, Nicolas CasadeiGND, Andrea TannapfelORCiDGND, Wolff-Helmut SchmiegelGND, Stephan HahnORCiDGND, Deepak VangalaORCiDGND
Parent Title (English):Molecular oncology
Publisher:FEBS Press, part of Wiley
Place of publication:Cambridge, Cambridgeshire
Document Type:Article
Date of Publication (online):2024/03/20
Date of first Publication:2023/08/21
Publishing Institution:Ruhr-Universität Bochum, Universitätsbibliothek
Tag:Open Access Fonds
CRC; EGFR; MEK; PDX; resistance; targeted therapy
First Page:2396
Last Page:2414
Article Processing Charge funded by the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of Ruhr-Universität Bochum.
Institutes/Facilities:Institut für Molekulare Gastroenterologische Onkologie
Zentrum für Hämatoonkologische Erkrankungen (ZHOE)
open_access (DINI-Set):open_access
faculties:Medizinische Fakultät
Licence (English):License LogoCreative Commons - CC BY 4.0 - Attribution 4.0 International