Pharmacologic profiling of patient-derived xenograft models of primary treatment-naïve triple-negative breast cancer

Sci Rep. 2020 Oct 21;10(1):17899. doi: 10.1038/s41598-020-74882-4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Disease Models, Animal
  • Drug Repositioning / methods
  • Female
  • Heterografts
  • High-Throughput Screening Assays / methods
  • Humans
  • Kinesin / antagonists & inhibitors
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Targeted Therapy
  • Neoplasm Transplantation
  • Quinuclidines
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / pathology*
  • Xenograft Model Antitumor Assays / methods*

Substances

  • 2-hydroxymethyl-2-methoxymethylazabicyclo(2.2.2)octan-3-one
  • Antineoplastic Agents
  • Quinuclidines
  • Kif11 protein, mouse
  • Kinesin