Skip to main content

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.

This is a preview of subscription content, access via your institution.

Fig. 1


  1. Janne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013;14(1):38–47.

    Article  CAS  PubMed  Google Scholar 

  2. Migliardi G, Sassi F, Torti D, Galimi F, Zanella ER, Buscarino M, et al. Inhibition of MEK and PI3K/mTOR suppresses tumor growth but does not cause tumor regression in patient-derived xenografts of RAS-mutant colorectal carcinomas. Clin Cancer Res. 2012;18(9):2515–25.

    Article  CAS  PubMed  Google Scholar 

  3. Shaul YD, Seger R. The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta. 2007;1773(8):1213–26.

    Article  CAS  PubMed  Google Scholar 

  4. Sforza V, Martinelli E, Ciardiello F, Gambardella V, Napolitano S, Martini G, et al. Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer. World J Gastroenterol. 2016;22(28):6345–61.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Queralt B, Cuyas E, Bosch-Barrera J, Massaguer A, de Llorens R, Martin-Castillo B, et al. Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer. Oncotarget. 2016;7(50):82185–99.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ursem C, Atreya CE, Van Loon K. Emerging treatment options for BRAF-mutant colorectal cancer. Gastrointest Cancer. 2018;8:13–23.

    PubMed  PubMed Central  Google Scholar 

Download references


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.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Cédric Rébé.

Additional information

Enhanced Digital Features

To view enhanced digital features for this article go to

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOC 36 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ledys, F., Derangère, V., Réda, M. et al. Anti-MEK and Anti-EGFR mAbs in RAS-Mutant Metastatic Colorectal Cancer: Case Series and Rationale. Adv Ther 36, 1480–1484 (2019).

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI:


  • Cetuximab
  • EGFR
  • KRAS
  • MEK
  • Trametinib