A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells
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Abstract
Intrinsic and/or acquired resistance represents one of the great challenges in targeted cancer therapy. A deeper understanding of the molecular biology of cancer has resulted in more efficient strategies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has also been observed in colorectal cancer patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block intrinsic resistance to BRAF inhibitors. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant colorectal cancer cells as a model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both known and novel responses. We primarily observe widespread up-regulation of receptor tyrosine kinases and metabolic pathways upon BRAF inhibition. These findings point to mechanisms by which the drug-treated cells switch energy sources and enter a quiescent-like state as a defensive response, while additionally compensating for the MAPK pathway inhibition.
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Acquired resistance to BRAF-targeted therapy is not limited to reactivation of MAPK signaling that drives aggressive cancer phenotypes, but also involves adaptive upregulation of metabolic pathways.
“Acquired resistance to BRAF-targeted therapy is not limited to reactivation of MAPK signaling that drives aggressive cancer phenotypes, but also involves adaptive upregulation of metabolic pathways [15,46].”
From Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer (2026) · cites this paper as [46]
Ressa et al. reported enhanced lipid metabolism and the TCA cycle activity upon BRAF inhibition using PLX4032 and/or gefitinib in CRC.
“Consistently, Ressa et al. reported enhanced lipid metabolism and the TCA cycle activity upon BRAF inhibition using PLX4032 and/or gefitinib in CRC [46].”
From Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer (2026) · cites this paper as [46]
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Flagged first, then by citations
Cited by
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Computational Analysis of Phosphoproteomics Data in Multi‐Omics Cancer Studies
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Multiomics profiling of paired primary and recurrent glioblastoma patient tissues
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“Acquired resistance to BRAF-targeted therapy is not limited to reactivation of MAPK signaling that drives aggressive cancer phenotypes, but also involves adaptive upregulation of metabolic pathways [15,46].”
Thermodynamic study of BRAF V600 mutations in colorectal cancer patients
Alasaifer, H. A., Sadawe, E. A., Almakhlufi, A. A., Bensaber, S. M., Bashein, A., Hermann, A., & Gbaj, A. M. (2018) · Pharmacy & Pharmacology International Journal · doi:10.15406/ppij.2018.06.00208
- Authors
- Ressa, A., Bosdriesz, E., de Ligt, J., Mainardi, S., Maddalo, G., Prahallad, A., Jager, M., de la Fonteijne, L., Fitzpatrick, M., Groten, S., Altelaar, A. F. M., Bernards, R., Cuppen, E., Wessels, L., & Heck, A. J. R.
- Affiliations
- Utrecht University (NL)
- The Netherlands Cancer Institute (NL)
- Corresponding author
- Wessels, Lodewyk
- Heck, Albert J.R.
- ORCID
- Venue
- Molecular & Cellular Proteomics
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 17
- Issue
- 10
- Pages
- 1892-1908
- ISSN
- 1535-9476 (ISSN-L)
- PMC
- PMC6166676
- OpenAlex
- W2757662346
- Cited by
- 17
- References
- 89
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 5 · 2018: 2
- FWCI
- 0.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular & Cellular Proteomics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- SSRN Electronic Journal (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (184.032.201)
- 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
- BRAF V600E mutation, EGFR inhibition, colorectal cancer, combination therapy, drug resistance, MAPK signaling, receptor tyrosine kinase, metabolic reprogramming, transcriptomics, proteomics, phosphoproteomics, multi-omics integration
- MeSH terms
- Cell Cycle, Drug Synergism, Humans, Models, Biological, Mutation, Colorectal Neoplasms, Down-Regulation, Gene Expression Regulation, Neoplastic, Phosphatidylinositol 3-Kinases, MAP Kinase Signaling System, Feedback, Physiological, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Cell Proliferation, Systems Biology, Proto-Oncogene Proteins c-akt, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Gene Knockout Techniques, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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