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Cited by 92Colorectal Cancer Treatments and StudiesMelanoma and MAPK PathwaysProtein Kinase Regulation and GTPase Signaling

MEK1/2 Inhibitors AS703026 and AZD6244 May Be Potential Therapies for KRAS Mutated Colorectal Cancer That Is Resistant to EGFR Monoclonal Antibody Therapy

Yoon, Juyong, Koo, Kyoung-Hwa, Choi, Kang-Yell·2011·Cancer Research
DOI 10.1158/0008-5472.can-10-3058

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Abstract

Epidermal growth factor receptor (EGFR) monoclonal antibodies (mAb) are used widely to treat metastatic colorectal cancer (mCRC) patients, but it is now clear that patients harboring K-ras mutation are resistant to EGFR mAbs such as cetuximab (Erbitux) and panitumumab (Vectibix). For this reason, current recommendations for patient care involve diagnosing the K-ras mutational status of patients prior to EGFR mAb therapy. In this study, we investigated the ability of two MEK inhibitors currently in clinical trials, AS703026 and AZD6244, to address the challenge posed by the resistance of K-ras mutated colorectal cancers to EGFR mAb. AS703026 and AZD6244 were tested in various cell-based assays and tumor xenograft studies, focusing on isogenic human colorectal tumor cell lines that expressed only WT or mutant K-Ras (D-WT or D-MUT). The EGFR mAb cetuximab inhibited the Ras-ERK pathway and proliferation of D-WT cells in vitro and in vivo, but it did not inhibit proliferation of D-MUT cells in either setting. In contrast, AS703026 and AZD6244 effectively inhibited the growth of D-MUT cells in vitro and in vivo by specific inhibition of the key MEK downstream target kinase ERK. Inhibition of MEK by AS703026 or AZD6244 also suppressed cetuximab-resistant colorectal cancer cells attributed to K-ras mutation both in vitro and in vivo. Our findings offer proof-of-concept for the use of MEK inhibitors as an effective therapy in K-ras mutated CRC. Cancer Res; 71(2); 445–53. ©2010 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 [42]

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Authors
Yoon, J., Koo, K.-H., & Choi, K.-Y.
Affiliations
Yonsei University (KR)
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2011-01-13
Volume
71
Issue
2
Pages
445-453
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-10-3058
OpenAlex
W2091935713
Cited by
92
References
48
Citations by year
2026: 2 · 2025: 2 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 3 · 2018: 7 · 2017: 6 · 2016: 7 · 2015: 8 · 2014: 15 · 2013: 12 · 2012: 12
FWCI
4.59
Type
journal article
Language
en
Open access
closed
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Merck
  • Yonsei University College of Medicine
Topics
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
MEK inhibitors, selumetinib, KRAS mutation, metastatic colorectal cancer, cetuximab resistance, panitumumab, Ras/ERK pathway, combination therapy
MeSH terms
Cetuximab, Animals, Antibodies, Monoclonal, Benzimidazoles, Humans, Male, Mice, Inbred BALB C, Mice, Nude, Mutation, Niacinamide, Genes, ras, Colorectal Neoplasms, Xenograft Model Antitumor Assays, Cell Line, Tumor, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Cell Growth Processes, Mice, Antibodies, Monoclonal, Humanized, ErbB Receptors

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