Primary and Acquired Resistance of Colorectal Cancer Cells to Anti-EGFR Antibodies Converge on MEK/ERK Pathway Activation and Can Be Overcome by Combined MEK/EGFR Inhibition

Troiani, Teresa; Napolitano, Stefania; Vitagliano, Donata; Morgillo, Floriana; Capasso, Anna; Sforza, Vincenzo; Nappi, Anna; Ciardiello, Davide; Ciardiello, Fortunato; Martinelli, Erika

doi:10.1158/1078-0432.ccr-13-2181

Cited by 104Colorectal Cancer Treatments and StudiesMelanoma and MAPK PathwaysLung Cancer Treatments and Mutations

Primary and Acquired Resistance of Colorectal Cancer Cells to Anti-EGFR Antibodies Converge on MEK/ERK Pathway Activation and Can Be Overcome by Combined MEK/EGFR Inhibition

Troiani, Teresa, Napolitano, Stefania, Vitagliano, Donata, Morgillo, Floriana, Capasso, Anna, Sforza, Vincenzo, Nappi, Anna, Ciardiello, Davide +2 more·2014·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-13-2181

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Abstract

Purpose: The EGFR-independent activation of the RAS/RAF/MEK/MAPK pathway is one of the resistance mechanisms to cetuximab. Experimental Design: We have evaluated, in vitro and in vivo, the effects of BAY 86-9766, a selective MEK1/2 inhibitor, in a panel of human colorectal cancer cell lines with primary or acquired resistance to cetuximab. Results: Among the colorectal cancer cell lines, five with a KRAS mutation (LOVO, HCT116, HCT15, SW620, and SW480) and one with a BRAF mutation (HT29) were resistant to the antiproliferative effects of cetuximab, whereas two cells (GEO and SW48) were highly sensitive. Treatment with BAY 86-9766 determined dose-dependent growth inhibition in all cancer cells, including two human colorectal cancer cells with acquired resistance to cetuximab (GEO-CR and SW48-CR), with the exception of HCT15 cells. Combined treatment with cetuximab and BAY 86-9766 induced a synergistic antiproliferative and apoptotic effects with blockade in the MAPK and AKT pathway in cells with either primary or acquired resistance to cetuximab. The synergistic antiproliferative effects were confirmed using other two selective MEK1/2 inhibitors, selumetinib and pimasertib, in combination with cetuximab. Moreover, inhibition of MEK expression by siRNA restored cetuximab sensitivity in resistant cells. In nude mice bearing established human HCT15, HCT116, SW48-CR, and GEO-CR xenografts, the combined treatment with cetuximab and BAY 86-9766 caused significant tumor growth inhibition and increased mice survival. Conclusion: These results suggest that activation of MEK is involved in both primary and acquired resistance to cetuximab and the inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance in patients with colorectal cancer. Clin Cancer Res; 20(14); 3775–86. ©2014 AACR.

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AS703026, AZD6244 and BAY86-9766 hinder the growth of mutant KRAS cells in vitro and in vivo by specifically suppressing ERK downstream of MEK.
“AS703026 (also known as pimasertib), AZD6244 (also known as selumetinib) and BAY86–9766 have a great ability to hinder the growth of mutant KRAS cells in vitro and in vivo by specifically suppressing the key target kinase ERK, which is downstream of MEK [30, 42].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [30]
The combination of selumetinib and cetuximab failed to achieve positive results in a clinical trial in refractory metastatic colorectal cancer patients with KRAS mutations.
“More importantly, the combination of selumetinib and cetuximab failed to achieve positive results in a clinical trial in refractory metastatic CRC patients with KRAS mutations [30, 101]”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [30]

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Authors: Troiani, T., Napolitano, S., Vitagliano, D., Morgillo, F., Capasso, A., Sforza, V., Nappi, A., Ciardiello, D., Ciardiello, F., & Martinelli, E.
Affiliations: University of Campania "Luigi Vanvitelli" (IT)
ORCID: Troiani, Teresa
Napolitano, Stefania
Morgillo, Floriana
Capasso, Anna
Sforza, Vincenzo
Nappi, Anna
Ciardiello, Davide
Ciardiello, Fortunato
Martinelli, Erika
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2014-07-14
Volume: 20
Issue: 14
Pages: 3775-3786
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-13-2181
OpenAlex: W2100968040
Cited by: 104
References: 41
Citations by year: 2026: 5 · 2025: 5 · 2024: 2 · 2023: 10 · 2022: 5 · 2021: 13 · 2020: 12 · 2019: 11 · 2018: 6 · 2017: 8 · 2016: 11 · 2015: 14 · 2014: 2
FWCI: 5.62
Type: journal article
Language: en
Open access: closed
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
Topics: Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords: colorectal cancer, cetuximab resistance, anti-EGFR monoclonal antibody, MEK/ERK signaling, MEK inhibitors, KRAS mutation, BRAF mutation, combination therapy, synergistic antiproliferative effect, apoptosis, AKT pathway, xenograft tumor growth inhibition
MeSH terms: Cetuximab, Animals, Antineoplastic Agents, Diphenylamine, Female, Humans, Mice, Inbred BALB C, Mice, Nude, Sulfonamides, Apoptosis, Drug Resistance, Neoplasm, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, RNA Interference, Cell Line, Tumor, Cell Proliferation, Gene Knockdown Techniques, Antibodies, Monoclonal, Humanized, ErbB Receptors

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Primary and Acquired Resistance of Colorectal Cancer Cells to Anti-EGFR Antibodies Converge on MEK/ERK Pathway Activation and Can Be Overcome by Combined MEK/EGFR Inhibition

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