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Triple Targeting of Breast Tumors Driven by Hormonal Receptors and HER2
Elena Shagisultanova1,2, Lyndsey S Crump1,2,3, Michelle Borakove1,2
1Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Abstract:
Breast cancers that express hormonal receptors (HR) and HER2 display resistance to targeted therapy. Tumor-promotional signaling from the HER2 and estrogen receptor (ER) pathways converges at the cyclin D1 and cyclin-dependent kinases (CDK) 4 and 6 complex, which drives cell-cycle progression and development of therapeutic resistance. Therefore, we hypothesized that co-targeting of ER, HER2, and CDK4/6 may result in improved tumoricidal activity and suppress drug-resistant subclones that arise on therapy. We tested the activity of the triple targeted combination therapy with tucatinib (HER2 small-molecule inhibitor), palbociclib (CKD4/6 inhibitor), and fulvestrant (selective ER degrader) in HR+/HER2+ human breast tumor cell lines and xenograft models. In addition, we evaluated whether triple targeted combination prevents growth of tucatinib or palbociclib-resistant subclones in vitro and in vivo Triple targeted combination significantly reduced HR+/HER2+ tumor cell viability, clonogenic survival, and in vivo growth. Moreover, survival of HR+/HER2+ cells that were resistant to the third drug in the regimen was reduced by the other two drugs in combination. We propose that a targeted triple combination approach will be clinically effective in the treatment of otherwise drug-resistant tumors, inducing robust responses in patients.
Insights
Combining targeted therapies against estrogen receptor (ER), HER2, and CDK4/6 may overcome resistance in HR+/HER2+ breast cancer. This triple therapy reduced tumor growth and prevented the emergence of drug-resistant cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Hormone receptor-positive (HR+) and HER2-positive (HER2+) breast cancers often develop resistance to targeted therapies.
- Signaling pathways of HER2 and estrogen receptor (ER) converge on the cyclin D1/cyclin-dependent kinases (CDK) 4 and 6 complex, driving cell-cycle progression and therapeutic resistance.
Purpose of the Study:
- To investigate the efficacy of a triple targeted combination therapy (tucatinib, palbociclib, fulvestrant) against HR+/HER2+ breast cancer.
- To determine if this combination therapy can prevent the development of drug-resistant subclones.
Main Methods:
- Testing the triple combination of tucatinib (HER2 inhibitor), palbociclib (CDK4/6 inhibitor), and fulvestrant (ER degrader) in HR+/HER2+ human breast cancer cell lines and xenograft models.
- Evaluating the prevention of tucatinib- or palbociclib-resistant subclone growth *in vitro* and *in vivo*.
Main Results:
- The triple targeted combination significantly reduced tumor cell viability, clonogenic survival, and *in vivo* tumor growth in HR+/HER2+ models.
- The combination therapy reduced the survival of HR+/HER2+ cells that were already resistant to one of the drugs.
Conclusions:
- A triple targeted combination approach may be clinically effective for treating drug-resistant breast tumors.
- This strategy has the potential to induce robust responses in patients with otherwise resistant breast cancer.
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