Identification of synergistic drug combinations using breast cancer patient-derived xenografts
Tia H Turner1,2, Mohammad A Alzubi1,3, J Chuck Harrell4,5,6,7
1Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA.
Abstract:
Compared with other breast cancer subtypes, triple-negative breast cancer (TNBC) is associated with relatively poor outcomes due to its metastatic propensity, frequent failure to respond to chemotherapy, and lack of alternative, targeted treatment options, despite decades of major research efforts. Our studies sought to identify promising targeted therapeutic candidates for TNBC through in vitro screening of 1,363 drugs in patient-derived xenograft (PDX) models. Using this approach, we generated a dataset that can be used to assess and compare responses of various breast cancer PDXs to many different drugs. Through a series of further drug screening assays and two-drug combination testing, we identified that the combination of afatinib (epidermal growth factor receptor (EGFR) inhibitor) and YM155 (inhibitor of baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5; survivin) expression) is synergistically cytotoxic across multiple models of basal-like TNBC and reduces PDX mammary tumor growth in vivo. We found that YM155 reduces EGFR expression in TNBC cells, shedding light on its potential mechanism of synergism with afatinib. Both EGFR and BIRC5 are highly expressed in basal-like PDXs, cell lines, and patients, and high expression of both genes reduces metastasis-free survival, suggesting that co-targeting of these proteins holds promise for potential clinical success in TNBC.
Insights
Researchers identified a promising combination therapy for triple-negative breast cancer (TNBC). Afatinib and YM155 synergistically kill TNBC cells and reduce tumor growth, offering new hope for targeted treatment options.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Triple-negative breast cancer (TNBC) presents significant challenges due to poor outcomes, metastasis, and resistance to chemotherapy.
- Lack of targeted therapies necessitates the identification of novel treatment strategies for TNBC.
- Patient-derived xenograft (PDX) models offer a valuable platform for preclinical drug screening.
Purpose of the Study:
- To identify novel targeted therapeutic candidates for triple-negative breast cancer (TNBC).
- To evaluate drug responses in patient-derived xenograft (PDX) models.
- To investigate synergistic drug combinations for TNBC treatment.
Main Methods:
- In vitro screening of 1,363 drugs using breast cancer PDX models.
- Subsequent drug screening assays and two-drug combination testing.
- Assessment of drug effects on tumor growth and gene expression in vivo and in vitro.
Main Results:
- The combination of afatinib (EGFR inhibitor) and YM155 (BIRC5 inhibitor) demonstrated synergistic cytotoxicity against basal-like TNBC models.
- This combination significantly reduced PDX mammary tumor growth in vivo.
- YM155 was found to reduce EGFR expression, elucidating a potential mechanism for the observed synergism.
Conclusions:
- Co-targeting of EGFR and BIRC5 (survivin) shows promise for TNBC treatment.
- High expression of both EGFR and BIRC5 correlates with reduced metastasis-free survival in TNBC patients.
- The afatinib and YM155 combination represents a potential clinical strategy for TNBC.
