Effect of Simvastatin on Cetuximab Resistance in Human Colorectal Cancer With KRAS Mutations
Abstract
BACKGROUND: Metastatic colorectal cancer (CRC) patients with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are resistant to treatment with cetuximab, a monoclonal antibody that targets the epidermal growth factor receptor. Statins have reported antitumor activity, but it is unknown whether simvastatin can reverse cetuximab resistance in KRAS mutant CRC. METHODS: Human CRC cell lines with KRAS mutations (LS153, LS174T, DLD1, LoVo, SW403, SW480, SNU175, and LS1034) or with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations (DiFi, SW48, HT29, and RKO) were used to test the effect of cetuximab, simvastatin, and cetuximab plus simvastatin on cell proliferation and apoptosis in vitro. Because BRAF(V600E) mutant may be responsible for cetuximab resistance in KRAS wild-type cells, we measured the growth of xenograft tumors originating from KRAS mutant and BRAF mutant cells in mice treated with cetuximab alone or plus simvastatin (n = 5 mice per treatment group). We used immunoblot assays to study RAS-regulated activation of BRAF protein after simvastatin treatment. All statistical tests were two-sided. RESULTS: Addition of simvastatin (0.2 μM) to cetuximab (0.03-1.0 μM) reduced cell proliferation of KRAS mutant (P < .001) but not of BRAF mutant CRC cells in vitro. Treatment of KRAS mutant cells with simvastatin reduced BRAF activity and induced apoptosis. Treatment with cetuximab and simvastatin reduced the growth of xenograft tumors originating from KRAS mutant cells compared with cetuximab alone (eg, for tumors originating from DLD1 cells, cetuximab vs cetuximab + simvastatin, mean tumor volume = 49.4 vs 20.2 cm(3), mean difference = 29.2 cm(3), 95% confidence interval = 19.7 to 38.5, P < .001); treatment with cetuximab alone or in combination with simvastatin had no effect on the growth of BRAF mutant tumors. CONCLUSION: Simvastatin may overcome cetuximab resistance in colon cancer cells with KRAS mutations by modulating BRAF activity and inducing apoptosis.
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The combination of simvastatin and cetuximab suppressed BRAF activity and reduced the proliferation of KRAS-mutant cells.
“The combination of simvastatin and cetuximab suppressed BRAF activity and reduced the proliferation of KRAS-mutant cells [49].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [49]
Inhibition of lipid synthesis or decomposition with simvastatin or glutaminase 1 inhibitor CB-839 significantly reduced tumour growth of CRC under cetuximab treatment.
“Inhibition of lipid synthesis or decomposition with simvastatin or glutaminase 1 inhibitor CB-839 significantly reduced tumour growth of CRC under cetuximab treatment [49, 50].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [49]
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References 43 · Cited by 103
- Authors
- Lee, J., Lee, I., Han, B., Park, J. O., Jang, J., Park, C., & Kang, W. K.
- Affiliations
- Samsung Medical Center (KR)
- Venue
- JNCI: Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-03
- Volume
- 103
- Issue
- 8
- Pages
- 674-688
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- OpenAlex
- W2125756326
- Cited by
- 103
- References
- 43
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 10 · 2022: 3 · 2021: 8 · 2020: 5 · 2019: 4 · 2018: 10 · 2017: 7 · 2016: 3 · 2015: 12 · 2014: 12 · 2013: 8 · 2012: 10
- FWCI
- 5.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- simvastatin, cetuximab resistance, KRAS mutation, colorectal cancer, BRAF V600E mutation, epidermal growth factor receptor, statins, combination therapy, apoptosis, xenograft tumor growth, metastatic colorectal cancer, cell proliferation inhibition, drug resistance reversal, anti-EGFR therapy, BRAF inhibitors
- MeSH terms
- Cetuximab, Animals, Antibodies, Monoclonal, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Mice, Inbred BALB C, Mutation, Plasmids, Proto-Oncogene Proteins, Transfection, Transplantation, Heterologous, Immunoblotting, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Apoptosis, ras Proteins, Drug Resistance, Neoplasm, Simvastatin, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Cell Proliferation, Mice, Antibodies, Monoclonal, Humanized
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