Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways
Open accessAbstract
Trastuzumab is a successful rationally designed ERBB2-targeted therapy. However, about half of individuals with ERBB2-overexpressing breast cancer do not respond to trastuzumab-based therapies, owing to various resistance mechanisms. Clinically applicable regimens for overcoming trastuzumab resistance of different mechanisms are not yet available. We show that the nonreceptor tyrosine kinase c-SRC (SRC) is a key modulator of trastuzumab response and a common node downstream of multiple trastuzumab resistance pathways. We find that SRC is activated in both acquired and de novo trastuzumab-resistant cells and uncover a novel mechanism of SRC regulation involving dephosphorylation by PTEN. Increased SRC activation conferred considerable trastuzumab resistance in breast cancer cells and correlated with trastuzumab resistance in patients. Targeting SRC in combination with trastuzumab sensitized multiple lines of trastuzumab-resistant cells to trastuzumab and eliminated trastuzumab-resistant tumors in vivo, suggesting the potential clinical application of this strategy to overcome trastuzumab resistance.
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SRC kinases can directly modulate many downstream targets including c-MYC, related to drug resistance and tumor cell survival.
“In addition to MAPK, SRC kinases can directly modulate many downstream targets including and c-MYC [19, 21, 22, 44], related to drug resistance and tumor cell survival.”
From Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer (2025) · cites this paper as [44]
The Discussion (page not provided) says SRC modulates downstream targets including c-MYC and links those pathways to tumor-cell survival. The Results also link SRC activation to trastuzumab resistance. The paper does not establish that SRC modulates c-MYC directly, so that mechanistic qualifier is unsupported. (LLM, conf=0.84)
Experimental — accuracy not yet measuredStudies in breast cancer revealed SRC as a common node downstream of multiple resistance pathways.
“Additionally, studies in breast cancer revealed SRC as a common node downstream of multiple resistance pathways [44].”
From Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer (2025) · cites this paper as [44]
PTEN was no longer capable of dephosphorylating and suppressing Src in trastuzumab-resistant HER2+ cells, and addition of a Src kinase inhibitor overcame trastuzumab resistance.
“In another study, the authors suggest that PTEN was no longer capable of dephosphorylating and suppressing Src in trastuzumab-resistant HER2+ cells, and the addition of a Src kinase inhibitor overcame trastuzumab resistance (Zhang et al., 2011).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Zhang et al., 2011
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- Authors
- Zhang, S., Huang, W.-C., Li, P., Guo, H., Poh, S.-B., Brady, S. W., Xiong, Y., Tseng, L.-M., Li, S.-H., Ding, Z., Sahin, A. A., Esteva, F. J., Hortobagyi, G. N., & Yu, D.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Yu, Dihua
- ORCID
- Venue
- Nature Medicine
- Published
- 2011-03-13
- Volume
- 17
- Issue
- 4
- Pages
- 461-469
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC3877934
- OpenAlex
- W2068326740
- Cited by
- 515
- References
- 54
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 19 · 2023: 22 · 2022: 23 · 2021: 25 · 2020: 25 · 2019: 23 · 2018: 39 · 2017: 33 · 2016: 43 · 2015: 48 · 2014: 51 · 2013: 53 · 2012: 53
- FWCI
- 30.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30CA16672, P50CA116199, P01CA099031, R01CA112567, P30CA016672)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- trastuzumab resistance, Src kinase, PTEN, PI3K signaling, HER2-positive breast cancer, acquired drug resistance, combination therapy, HER2-targeted therapy
- MeSH terms
- Trastuzumab, Antibodies, Monoclonal, Antineoplastic Agents, Breast Neoplasms, Enzyme Activation, Female, Humans, Models, Biological, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, src-Family Kinases, Cell Line, Tumor, Antibodies, Monoclonal, Humanized
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