Oncogene Overdose: Too Much of a Bad Thing for Oncogene-Addicted Cancer Cells
Open accessAbstract
Acquired resistance to targeted inhibitors remains a major, and inevitable, obstacle in the treatment of oncogene-addicted cancers. Newer-generation inhibitors may help overcome resistance mutations, and inhibitor combinations can target parallel pathways, but durable benefit to patients remains elusive in most clinical scenarios. Now, recent studies suggest a third approach may be available in some cases—exploitation of oncogene overexpression that may arise to promote resistance. Here, we discuss the importance of maintaining oncogenic signaling at “just-right” levels in cells, with too much signaling, or oncogene overdose, being potentially as detrimental as too little. This is highlighted in particular by recent studies of mutant-BRAF in melanoma and the fusion kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) in anaplastic large cell lymphoma. Oncogene overdose may be exploitable to prolong tumor control through intermittent dosing in some cases, and studies of acute lymphoid leukemias suggest that it may be specifically pharmacologically inducible.
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Activating the MAPK pathway by mutant KRAS and the PI3K pathway by PIK3CA mutation with Her2 amplification may be harmful due to too much oncogene signaling.
“Because cytoplasmic KRAS localization suppresses KRAS–MAPK pathway activity at low levels, activating the MAPK pathway by mutant KRAS and the PI3K pathway by PIK3CA mutation with Her2 amplification may be harmful due to too much oncogene signaling45,46.”
From Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization (2025) · cites this paper as [46]
The “MAPK cascade and the Goldilocks principle” section (page unavailable) says excessive RAS–RAF–MEK–ERK signaling can cause senescence, supporting the idea that too much oncogene signaling may be harmful. It does not address the specific combination of mutant KRAS, PIK3CA mutation, and HER2 amplification or establish that activating both pathways in that setting is harmful. (LLM, conf=0.86)
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Oxygen therapy post-cardiac arrest: The ‘Goldilocks’ principle?
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Activation of self-reactive B cells and autoimmune diseases.
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Flagged first, then by citations
Cited by
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Paradoxical roles of cyclin D1 in DNA stability
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DUSP4 protects BRAF- and NRAS-mutant melanoma from oncogene overdose through modulation of MITF
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Brd4::Nutm1 fusion gene initiates NUT carcinoma in vivo
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do Prado-Souza, L. F. L., Ferraz, L. S., Tortelli, T. C., Ribeiro, C. A. J., Amaral, D. T., Arruda, D. C., de Oliveira, E. A., Chammas, R. J., Maria–Engler, S. S., & Rodrigues, T. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26062675 · Cited by 9 · see citing works
Keller, R. R., & Gunther, E. J. (2019) · Cell Reports · doi:10.1016/j.celrep.2018.12.096 · Cited by 9 · see citing works
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Wallace, K. A. (2020) · doi:10.21007/etd.cghs.2020.0495 · Cited by 1 · see citing works
Brd4::Nutm1 fusion gene initiates NUT carcinoma in vivoPreprint
Zheng, D., Elnegiry, A. A., Luo, C., Bendahou, M. A., Xie, L., Bell, D., Takahashi, Y., Hanna, E. Y., Mias, G. I., Tsoi, M. F., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.07.29.551125
The road less traveled: activating an oncogenic kinase
Paul, M., & Fruman, D. A. (2023) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2023.07.005
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Sridhar, S., Chan, A. S. Y., & Jeyasekharan, A. D. D. (2025) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-25-0064
The Fitness Cost of Therapeutic Resistance in Cancer: A Systematic ReviewPreprint
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- Authors
- Amin, A. D., Rajan, S. S., Groysman, M. J., Pongtornpipat, P., & schatz, J. H.
- Affiliations
- University of Miami (US)
- University of Arizona Cancer Center (US)
- BIO5 Institute (US)
- Corresponding author
- schatz, Jonathan H.
- Venue
- Biomarkers in Cancer
- Publisher
- SAGE Publications
- Published
- 2015-01
- Volume
- 7s2
- Issue
- Suppl 2
- Pages
- BIC.S29326
- ISSN
- 1179-299X (ISSN-L)
- PMC
- PMC4681422
- OpenAlex
- W2215206605
- Cited by
- 25
- References
- 86
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 2 · 2019: 2 · 2016: 4
- FWCI
- 0.24
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Biomarkers in Cancer (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Cancer Institute (R01CA190696)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- oncogene addiction, acquired drug resistance, targeted therapy resistance, melanoma, NPM-ALK, anaplastic large cell lymphoma, intermittent dosing, acute lymphoblastic leukemia, oncogenic signaling
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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