Related Experiment Video
Updated: Jun 26, 2025
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Evaluation of Copanlisib in Combination with Eribulin in Triple-negative Breast Cancer Patient-derived Xenograft
Zhanfang Guo1, Jingqin Luo2, R Jay Mashl3
1Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
Abstract:
The PI3K pathway regulates essential cellular functions and promotes chemotherapy resistance. Activation of PI3K pathway signaling is commonly observed in triple-negative breast cancer (TNBC). However previous studies that combined PI3K pathway inhibitors with taxane regimens have yielded inconsistent results. We therefore set out to examine whether the combination of copanlisib, a clinical grade pan-PI3K inhibitor, and eribulin, an antimitotic chemotherapy approved for taxane-resistant metastatic breast cancer, improves the antitumor effect in TNBC. A panel of eight TNBC patient-derived xenograft (PDX) models was tested for tumor growth response to copanlisib and eribulin, alone or in combination. Treatment-induced signaling changes were examined by reverse phase protein array, immunohistochemistry (IHC) and 18F-fluorodeoxyglucose PET (18F-FDG PET). Compared with each drug alone, the combination of eribulin and copanlisib led to enhanced tumor growth inhibition, which was observed in both eribulin-sensitive and -resistant TNBC PDX models, regardless of PI3K pathway alterations or PTEN status. Copanlisib reduced PI3K signaling and enhanced eribulin-induced mitotic arrest. The combination enhanced induction of apoptosis compared with each drug alone. Interestingly, eribulin upregulated PI3K pathway signaling in PDX tumors, as demonstrated by increased tracer uptake by 18F-FDG PET scan and AKT phosphorylation by IHC. These changes were inhibited by the addition of copanlisib. These data support further clinical development for the combination of copanlisib and eribulin and led to a phase I/II trial of copanlisib and eribulin in patients with metastatic TNBC.
Significance:
In this research, we demonstrated that the pan-PI3K inhibitor copanlisib enhanced the cytotoxicity of eribulin in a panel of TNBC PDX models. The improved tumor growth inhibition was irrespective of PI3K pathway alteration and was corroborated by the enhanced mitotic arrest and apoptotic induction observed in PDX tumors after combination therapy compared with each drug alone. These data provide the preclinical rationale for the clinical testing in TNBC.
Insights
The combination of copanlisib and eribulin significantly inhibits triple-negative breast cancer (TNBC) growth, enhancing antitumor effects beyond individual treatments. This novel combination therapy shows promise for TNBC patients, irrespective of specific PI3K pathway alterations.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The PI3K pathway is crucial for cell function and chemotherapy resistance, frequently activated in triple-negative breast cancer (TNBC).
- Previous attempts to combine PI3K inhibitors with taxanes in TNBC have shown inconsistent outcomes.
- Eribulin is an antimitotic chemotherapy effective in taxane-resistant metastatic breast cancer.
Purpose of the Study:
- To evaluate the efficacy of combining copanlisib, a pan-PI3K inhibitor, with eribulin in TNBC.
- To investigate the impact of this combination on tumor growth and signaling pathways in TNBC models.
Main Methods:
- Testing copanlisib and eribulin, alone and in combination, on eight TNBC patient-derived xenograft (PDX) models.
- Analyzing treatment-induced signaling changes using reverse phase protein array, IHC, and 18F-FDG PET.
Main Results:
- The combination of eribulin and copanlisib demonstrated enhanced tumor growth inhibition in TNBC PDX models, including those resistant to eribulin.
- Copanlisib suppressed PI3K signaling and amplified eribulin-induced mitotic arrest and apoptosis.
- Eribulin was observed to upregulate PI3K signaling, an effect counteracted by copanlisib.
Conclusions:
- The combination of copanlisib and eribulin provides a strong preclinical rationale for clinical development in TNBC.
- This combination therapy offers a promising strategy for metastatic TNBC, regardless of PI3K pathway status.
- A Phase I/II clinical trial is underway to further investigate this combination in TNBC patients.
