Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer
Open accessAbstract
SUMMARY Kinase inhibitors have limited success in cancer treatment because tumors circumvent their action. Using a quantitative proteomics approach, we assessed kinome activity in response to MEK inhibition in triple negative breast cancer (TNBC) cells and genetically engineered mice (GEMMs). MEK inhibition caused acute ERK activity loss, resulting in rapid c-Myc degradation that induced expression and activation of several receptor tyrosine kinases (RTKs). RNAi knockdown of ERK or c-Myc mimicked RTK induction by MEK inhibitors, whereas prevention of proteasomal c-Myc degradation blocked kinome reprogramming. MEK inhibitor-induced RTK stimulation overcame MEK2 but not MEK1 inhibition, reactivating ERK and producing drug resistance. The C3Tag GEMM for TNBC similarly induced RTKs in response to MEK inhibition. The inhibitor-induced RTK profile suggested a kinase inhibitor combination therapy that produced GEMM tumor apoptosis and regression where single agents were ineffective. This approach defines mechanisms of drug resistance, allowing rational design of combination therapies for cancer.
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Activation of FOXO transcription factors or downregulation of MYC can trigger feedback activation of RTK transcription following inhibition of PI3K/AKT or MEK pathways.
“Furthermore, early studies have shown that activation of FOXO transcription factors or downregulation of MYC can trigger feedback activation of RTK transcription following inhibition of the PI3K/AKT or MEK pathways,27,28”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [28]
Upon K-Ras inhibition, relief of ERK-mediated negative feedback promotes expression of RTKs, which in turn reactivates Ras signaling to confer therapeutic resistance.
“Upon K-Ras inhibition, the relief of ERK-mediated negative feedback promotes the expression of RTKs, which in turn reactivates Ras signaling to confer therapeutic resistance.80,81”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [80]
Adaptive resistance, in which the inhibited pathway is reactivated due to induction of RTKs/RTK ligand genes, is a common form of intrinsic resistance.
“Adaptive resistance (termed “rebound” by some investigators), in which the inhibited pathway is reactivated due to induction of RTKs/RTK ligand genes, is a common form of intrinsic resistance (Anderson et al., 2017; Duncan et al., 2012; Lin et al., 2015; Manchado et al., 2016; Nazarian et al., 2010; Sun et al., 2014; Zawistowski et al., 2017).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Duncan et al., 2012
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- Authors
- Duncan, J. S., Whittle, M. C., Nakamura, K., Abell, A. N., Midland, A. A., Zawistowski, J. S., Johnson, N. L., Granger, D. A., Jordan, N. V., Darr, D. B., Usary, J., Kuan, P.-F., Smalley, D. M., Major, B., He, X., Hoadley, K. A., Zhou, B., Sharpless, N. E., Perou, C. M., Kim, W. Y., Gomez, S. M., Chen, X., Jin, J., Frye, S. V., Earp, H. S., Graves, L. M., & Johnson, G. L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Johnson, Gary L.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 149
- Issue
- 2
- Pages
- 307-321
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3328787
- OpenAlex
- W2165575701
- Semantic Scholar
- e05778f479eecd34cbc1292417de2fc71c0b7355
- Cited by
- 732
- References
- 33
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- FWCI
- 26.59
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- journal article
- Language
- en
- Open access
- bronze
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- Funders
- National Institutes of Health (CA58223)
- Canadian Institutes of Health Research
- National Cancer Institute (CA-58223, CA 71341, U54CA156735, F31CA165595, P50CA058223, P30CA016086, T32CA071341)
- National Institute of General Medical Sciences (R01GM030324, GM 30324, R01GM101141, R37GM030324, T32GM007040, GM007040)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-37871, R01DK037871)
- National Institute of Environmental Health Sciences (P30ES010126)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- triple-negative breast cancer, MEK inhibition, kinome reprogramming, receptor tyrosine kinase, c-Myc degradation, ERK signaling, drug resistance, combination therapy, kinase inhibitor resistance, genetically engineered mouse models, tumor cell apoptosis
- MeSH terms
- Sorafenib, Animals, Antineoplastic Agents, Benzenesulfonates, Benzimidazoles, Breast Neoplasms, Disease Models, Animal, Female, Humans, Male, Niacinamide, Phenylurea Compounds, Protein Kinases, Pyridines, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, Drug Resistance, Neoplasm, Proteome, Receptor Protein-Tyrosine Kinases, Protein Kinase Inhibitors, Extracellular Signal-Regulated MAP Kinases, MAP Kinase Kinase 1, Mice
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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