CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer Academic Article uri icon

abstract

  • Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.

authors

  • Sanij, E
  • Hannan, KM
  • Xuan, J
  • Yan, S
  • Ahern, JE
  • Trigos, AS
  • Brajanovski, N
  • Son, J
  • Chan, KT
  • Kondrashova, O
  • Lieschke, E
  • Wakefield, MJ
  • Frank, D
  • Ellis, Sarah
  • Cullinane, C
  • Kang, J
  • Poortinga, G
  • Nag, P
  • Deans, AJ
  • Khanna, KK
  • Mileshkin, L
  • McArthur, GA
  • Soong, J
  • Berns, EMJJ
  • Hannan, RD
  • Scott, CL
  • Sheppard, KE
  • Pearson, RB

publication date

  • 2020

has subject area