TY - JOUR
T1 - Pharmacologic profiling of patient-derived xenograft models of primary treatment-naïve triple-negative breast cancer
AU - Powell, Reid T.
AU - Redwood, Abena
AU - Liu, Xuan
AU - Guo, Lei
AU - Cai, Shirong
AU - Zhou, Xinhui
AU - Tu, Yizheng
AU - Zhang, Xiaomei
AU - Qi, Yuan
AU - Jiang, Yan
AU - Echeverria, Gloria
AU - Feng, Ningping
AU - Ma, Xiao Yan
AU - Giuliani, Virginia
AU - Marszalek, Joseph R.
AU - Heffernan, Timothy P.
AU - Vellano, Christopher P.
AU - White, Jason B.
AU - Stephan, Clifford
AU - Davies, Peter J.
AU - Moulder, Stacy
AU - Symmans, W. Fraser
AU - Chang, Jeffrey T.
AU - Piwnica-Worms, Helen
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Triple-negative breast cancer (TNBC) accounts for 15–20% of breast cancer cases in the United States, lacks targeted therapeutic options, and is associated with a 40–80% risk of recurrence. Thus, identifying actionable targets in treatment-naïve and chemoresistant TNBC is a critical unmet medical need. To address this need, we performed high-throughput drug viability screens on human tumor cells isolated from 16 patient-derived xenograft models of treatment-naïve primary TNBC. The models span a range of TNBC subtypes and exhibit a diverse set of putative driver mutations, thus providing a unique patient-derived, molecularly annotated pharmacologic resource that is reflective of TNBC. We identified therapeutically actionable targets including kinesin spindle protein (KSP). The KSP inhibitor targets the mitotic spindle through mechanisms independent of microtubule stability and showed efficacy in models that were resistant to microtubule inhibitors used as part of the current standard of care for TNBC. We also observed subtype selectivity of Prima-1Met, which showed higher levels of efficacy in the mesenchymal subtype. Coupling pharmacologic data with genomic and transcriptomic information, we showed that Prima-1Met activity was independent of its canonical target, mutant p53, and was better associated with glutathione metabolism, providing an alternate molecularly defined biomarker for this drug.
AB - Triple-negative breast cancer (TNBC) accounts for 15–20% of breast cancer cases in the United States, lacks targeted therapeutic options, and is associated with a 40–80% risk of recurrence. Thus, identifying actionable targets in treatment-naïve and chemoresistant TNBC is a critical unmet medical need. To address this need, we performed high-throughput drug viability screens on human tumor cells isolated from 16 patient-derived xenograft models of treatment-naïve primary TNBC. The models span a range of TNBC subtypes and exhibit a diverse set of putative driver mutations, thus providing a unique patient-derived, molecularly annotated pharmacologic resource that is reflective of TNBC. We identified therapeutically actionable targets including kinesin spindle protein (KSP). The KSP inhibitor targets the mitotic spindle through mechanisms independent of microtubule stability and showed efficacy in models that were resistant to microtubule inhibitors used as part of the current standard of care for TNBC. We also observed subtype selectivity of Prima-1Met, which showed higher levels of efficacy in the mesenchymal subtype. Coupling pharmacologic data with genomic and transcriptomic information, we showed that Prima-1Met activity was independent of its canonical target, mutant p53, and was better associated with glutathione metabolism, providing an alternate molecularly defined biomarker for this drug.
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U2 - 10.1038/s41598-020-74882-4
DO - 10.1038/s41598-020-74882-4
M3 - Article
C2 - 33087803
AN - SCOPUS:85093866434
SN - 2045-2322
VL - 10
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 17899
ER -