Identification of synergistic drug combinations using breast cancer patient-derived xenografts.
Tia H TurnerMohammad A AlzubiJ Chuck HarrellPublished in: Scientific reports (2020)
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.
Keyphrases
- epidermal growth factor receptor
- tyrosine kinase
- advanced non small cell lung cancer
- poor prognosis
- small cell lung cancer
- cancer therapy
- free survival
- cell cycle arrest
- end stage renal disease
- ejection fraction
- drug induced
- newly diagnosed
- squamous cell carcinoma
- oxidative stress
- cell death
- prognostic factors
- drug delivery
- type diabetes
- high throughput
- peritoneal dialysis
- quality improvement
- cell proliferation
- endoplasmic reticulum stress
- skeletal muscle
- adverse drug
- locally advanced
- rectal cancer
- insulin resistance
- metabolic syndrome
- signaling pathway
- young adults