Anti-MEK and Anti-EGFR mAbs in RAS-Mutant Metastatic Colorectal Cancer: Case Series and Rationale
KRAS (Kirsten rat sarcoma viral oncogene) or BRAF (v-raf murine sarcoma viral oncogene homolog B1) constitutive activation leads to anti-EGFR (epidermal growth factor receptor) therapy resistance of metastatic colorectal cancer patients. In this article we investigate the effects of anti-MEK (mitogen-activated protein kinase) antibody (trametinib) combined with anti-EGFR (cetuximab) on colon cancer cell lines with different RAS statuses. Even though cetuximab has no effect on RAS cell viability and ERK (extracellular-signal-regulated kinase) phosphorylation (one of the last kinases of the EGFR pathway), trametinib can induce cell death and inhibit the activation of ERK alone or in combination with cetuximab. In a more pathologic context, we observed that KRAS colon cancer patient biopsies treated ex vivo with trametinib and cetuximab also present less ERK phosphorylation. Finally, nine ovarian, endometrial and colon cancer patients with different KRAS statuses were treated with anti-EGFR/anti-MEK combination off label after molecular tumor board decision. KRAS exon 2 patients have significantly longer PFS (progression-free survival) than with previous lines of treatments. We believe that such observations provide a rationale for designing a clinical trial to test this association in RAS exon 2 mutated cancers.
KeywordsCetuximab EGFR KRAS MEK Trametinib
We thank the CGFL Pathology Department for providing patient samples. We thank Isabel Gregoire (CGFL) for carefully reading the manuscript. We also thank all the participating patients of the study.
This study was supported by the “Ligue Contre le Cancer.”. The article processing charges were paid by the Centre GF Leclerc thanks to the Ligue Contre le Cancer.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Fanny Ledys, Valentin Derangère, Manon Réda, Jean-Florian Guion, Romily Milliex, Valérie Roux, Emeric Limagne, Laurent Arnould, Leila Bengrine, Cédric Rébé and François Ghiringhelli declare that they have no conflict of interest.
Compliance with Ethics Guidelines
All procedures performed in this study involving human participants and material were in accordance with the ethical standards of the molecular tumor board research committee of the Centre GF Leclerc and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
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