Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors
Open accessAbstract
Using transgenic mouse models, cell line-based functional studies, and clinical specimens, we show that cyclin D1/CDK4 mediate resistance to targeted therapy for HER2-positive breast cancer. This is overcome using CDK4/6 inhibitors. Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC1 activity. This relieves feedback inhibition of upstream EGFR family kinases, resensitizing tumors to EGFR/HER2 blockade. Consequently, dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of TSC2 phosphorylation and hence mTORC1/S6K/S6RP activity. The suppression of both Rb and S6RP enhances G1 arrest and a phenotype resembling cellular senescence. In vivo, CDK4/6 inhibitors sensitize patient-derived xenograft tumors to HER2-targeted therapies and delay tumor recurrence in a transgenic model of HER2-positive breast cancer.
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In a mouse model of breast cancer, CDK4/6 inhibition-driven cellular senescence also triggered antitumour immunity, mediated by suppression of regulatory T cells and re-expression of endogenous retroviral elements, which elicited an interferon response.
“Moreover, in a mouse model of breast cancer, CDK4/6 inhibition- driven cellular senescence also triggered antitumour immunity, mediated by suppression of regulatory Tcells and re- expression of endogenous retroviral elements, which elicited an interferon response 106,153 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [106]
The Results report a senescence-like phenotype after CDK4/6 inhibition in breast cancer cells, and the paper studies CDK4/6 inhibition in mouse models. But the Discussion says immune clearance of senescent cells remains a possibility to investigate; it does not establish antitumour immunity or the claimed regulatory T-cell, retroviral-element, and interferon mechanisms. The supplied copy gives section labels but no page numbers. (LLM, conf=0.90)
Experimental — accuracy not yet measuredCDK4 is substantially overexpressed in glioblastoma, breast and ovarian cancers.
“CDK4, one of the main controllers of cell cycle entry, is substantially overexpressed in glioblastoma, breast and ovarian cancers, making it an attractive therapeutic target27, 28, 29.”
In some models, resistance to signaling pathway inhibitors can be overcome by adding CDK4/6 inhibitors.
“In some of these models, resistance can be overcome by including CDK4/6 inhibitors in the treatment (Finn et al., 2009; Goel et al., 2016; Kwong et al., 2012; Vora et al., 2014; Zhou et al., 2017).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Goel et al., 2016
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- Authors
- Goel, S., Wang, Q., Watt, A. C., Tolaney, S. M., Dillon, D. A., Li, W., Ramm, S., Palmer, A. C., Yuzugullu, H., Varadan, V., Tuck, D., Harris, L. N., Wong, K.-K., Liu, X. S., Sicinski, P., Winer, E. P., Krop, I. E., & Zhao, J. J.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Case Comprehensive Cancer Center (US)
- Yale University (US)
- Case Western Reserve University (US)
- Broad Institute (US)
- Corresponding author
- Goel, Shom
- Zhao, Jean J.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 29
- Issue
- 3
- Pages
- 255-269
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4794996
- OpenAlex
- W2299045691
- Cited by
- 470
- References
- 26
- Citations by year
- 2026: 29 · 2025: 47 · 2024: 32 · 2023: 51 · 2022: 60 · 2021: 46 · 2020: 64 · 2019: 46 · 2018: 50 · 2017: 30 · 2016: 15
- FWCI
- 41.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (P50 CA168504, CA172461, U01CA180980, R01 CA083688, P01 CA080111)
- Susan G. Komen (SAC 10005)
- Breast Cancer Research Foundation
- Aid for Cancer Research
- Institutional Research Grant of Hollings Cancer Center
- Medical University of South Carolina
- National Health and Medical Research Council of Australia
- Genentech
- AstraZeneca
- Acetylon
- Gilead Pharmaceuticals
- Novartis
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- HER2-positive breast cancer, CDK4/6 inhibitors, treatment resistance, cyclin D1, CDK4, retinoblastoma protein phosphorylation, TSC2 phosphorylation, mTORC1, G1 cell cycle arrest, cellular senescence, patient-derived xenografts, transgenic mouse model
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Breast Neoplasms, Disease Models, Animal, Female, Humans, Mice, Nude, Mice, Transgenic, Neoplasm Recurrence, Local, Phosphorylation, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Tumor Suppressor Proteins, Cell Line, Tumor, Multiprotein Complexes, Protein Kinase Inhibitors, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Mice, TOR Serine-Threonine Kinases, ErbB Receptors
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