BET, SRC, and BCL2 family inhibitors are synergistic drug combinations with PARP inhibitors in ovarian cancer

EBioMedicine. 2020 Oct;60:102988. doi: 10.1016/j.ebiom.2020.102988. Epub 2020 Sep 11.

Abstract

Background: Homologous recombination deficiencies (HRD) are present in approximately half of epithelial ovarian cancers, for which PARP inhibitors (PARPi) are becoming a preferred treatment option. However, a considerable proportion of these carcinomas acquire resistance or harbour de novo resistance, posing a significant challenge to treatment.

Methods: To identify new combinatorial therapeutics to overcome resistance to PARPi, we employed high-throughput conditional RNAi and drug screening of patient-derived ovarian cancer cells. To prioritise clinically relevant drug combinations, we integrated empirical validation with analysis of The Cancer Genome Atlas (TCGA) and Genomics of Drug Sensitivity in Cancer (GDSC) datasets to nominate candidate targets and drugs, reaching three main findings.

Findings: Firstly, we found that the PARPi rucaparib enhanced the effect of BET inhibitors (CPI-203 & CPI-0610) irrespective of clinical subtype or HRD status. Additional drug combination screens identified that dasatinib, a non-receptor tyrosine kinase inhibitor, augmented the effects of rucaparib and BET inhibitors, proposing a potential broadly applicable triple-drug combination for high-grade serous and clear cell ovarian carcinomas. Secondly, rucaparib synergised with the BCL2 family inhibitor navitoclax, with preferential activity in ovarian carcinomas that harbour alterations in BRCA1/2, BARD1, or MSH2/6. Thirdly, we identified potentially antagonistic drug combinations between the PARPi rucaparib and vinca alkaloids, anthracyclines, and antimetabolites, cautioning their use in the clinic.

Interpretation: These findings propose therapeutic strategies to address PARP inhibitor resistance using agents that are already approved or are in clinical development, with the potential for rapid translation to benefit a broad population of ovarian cancer patients.

Keywords: Dasatinib; Drug combinations; Navitoclax; Ovarian cancer; Poly(ADP-ribose) Polymerase Inhibitors; Rucaparib.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Synergism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Transcriptome
  • Xenograft Model Antitumor Assays
  • src-Family Kinases / antagonists & inhibitors

Substances

  • Antineoplastic Agents
  • BCL2 protein, human
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Protein Kinase Inhibitors
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bromodomain and extra-terminal domain protein, human
  • src-Family Kinases