Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers
Open accessAbstract
Molecular targeted drugs are clinically effective anti-cancer therapies. However, tumours treated with single agents usually develop resistance. Here we use colorectal cancer (CRC) as a model to study how the acquisition of resistance to EGFR-targeted therapies can be restrained. Pathway-oriented genetic screens reveal that CRC cells escape from EGFR blockade by downstream activation of RAS-MEK signalling. Following treatment of CRC cells with anti-EGFR, anti-MEK or the combination of the two drugs, we find that EGFR blockade alone triggers acquired resistance in weeks, while combinatorial treatment does not induce resistance. In patient-derived xenografts, EGFR-MEK combination prevents the development of resistance. We employ mathematical modelling to provide a quantitative understanding of the dynamics of response and resistance to these single and combination therapies. Mechanistically, we find that the EGFR-MEK Combo blockade triggers Bcl-2 and Mcl-1 downregulation and initiates apoptosis. These results provide the rationale for clinical trials aimed at preventing rather than intercepting resistance.
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Combination treatment with MEK and EGFR inhibitors seems to be a possible strategy to overcome the multifaceted clonal heterogeneity in tumours.
“Encouragingly, combination treatment with MEK and EGFR inhibitors seems to be a possible strategy to overcome the multifaceted clonal heterogeneity in tumours [29, 101].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [29]
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References 35 · Cited by 122
- Authors
- Misale, S., Bozic, I., Tong, J., Peraza-Penton, A., Lallo, A., Baldi, F., Lin, K. H., Truini, M., Trusolino, L., Bertotti, A., Di Nicolantonio, F., Nowak, M. A., Zhang, L., Wood, K. C., & Bardelli, A.
- Affiliations
- IFOM (IT)
- University of Pittsburgh (US)
- Duke University (US)
- Candiolo Cancer Institute (IT)
- Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT)
- Harvard University (US)
- Corresponding author
- Bardelli, Alberto
- ORCID
- Venue
- Nature Communications
- Published
- 2015-09-22
- Volume
- 6
- Issue
- 1
- Pages
- 8305-8305
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4595628
- OpenAlex
- W2184198667
- Cited by
- 122
- References
- 35
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 10 · 2023: 9 · 2022: 4 · 2021: 11 · 2020: 16 · 2019: 8 · 2018: 16 · 2017: 20 · 2016: 20
- FWCI
- 8.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- European Commission (115749, 602901)
- Ministero della Salute
- Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN 2010-2011 “, 2010-2011, (PRIN 2010))
- Associazione Italiana per la Ricerca sul Cancro (12812, PRIN 2010)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- anti-EGFR therapy, acquired drug resistance, colorectal cancer, combination therapy, patient-derived xenografts, Bcl-2 downregulation, apoptosis, resistance prevention
- MeSH terms
- Cetuximab, Panitumumab, Animals, Antibodies, Monoclonal, Antineoplastic Agents, Cell Line, Humans, Neoplasms, Experimental, Transplantation, Heterologous, Colorectal Neoplasms, Drug Resistance, Neoplasm, Mitogen-Activated Protein Kinase Kinases, Intracellular Signaling Peptides and Proteins, Mice, ErbB Receptors
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