Targeting MYCN over-expression with BRD4 inhibition in the proliferative C5 subtype of high grade serous ovarian cancer (HGSOC)

Gwo-Yaw Ho, Olga Kondrashova, Cassandra J Vandenberg, Elizabeth Kyran, Elizabeth Lieschke, Valerie Heong, Michael Milevinskiy, Tony A. Papenfuss, John Weroha, Mark Dawson, David D L Bowtell, Holly E. Barker, Matthew J Wakefield, Clare L Scott

Research output: Contribution to conferencePosterpeer-review

Abstract

Background:
Gene expression profiling of HGSOC revealed four molecularly distinct subtypes (C1, C2, C4 and C5) 1. MYCN over-expression, which can drive a mesenchymal or epithelial-mesenchymal transitional prone phenotype, is a key feature in the C5 subtype of HGSOC 2. Targeting MYCN and MYC over-expression with the BRD4 inhibitor (I-BET-762) has efficacy in ovarian cancer pre-clinical models 3. We aim to explore the mechanism of activity and resistance of I-BET-762 in C5 HGSOC, with a focus on the pro-survival pathway, using BH3-mimetic therapy (ABT-199).

Methods:
Six well-characterised C5 HGSOC patient derived xenograft (PDX) models were tested for in vivo response to single agent I-BET-762 (25mg/kg on alternate days for 21 days) or combination I-BET-762/ABT-199 (100mg/kg Mon to Fri for 21 days) regimens. RNA and DNA samples were prepared.

Results:
Surprisingly, only one of six C5 PDX responded to single agent I-BET-762. Two of five non-I-BET-762 responders showed evidence of tumour regression with I-BET-762 and ABT-199 combination, albeit short-lived responses. Short term harvest experiments were performed with the one I-BET-762 responder and one PDX that responded to combination I-BET-762 and ABT-199 treatment. RNASeq, ATACSeq and ChIPSeq were performed and analysis is currently underway to elucidate the underlying mechanisms of activity.

Conclusions:
BRD4 inhibition with I-BET-762 is only an effective treatment in a specific subset of HGSOC. The escape from the apoptotic pathway may be one of the mechanisms of drug resistance to I-BET-762. Understanding this mechanism may be crucial in establishing a more effective combination regimen.
Original languageEnglish
Publication statusPublished - Nov 2018
EventBiennial Meeting of the International Gynecologic Cancer Society - Kyoto, Japan
Duration: 14 Sep 201816 Sep 2018
https://igcs2018.com

Conference

ConferenceBiennial Meeting of the International Gynecologic Cancer Society
Abbreviated titleIGCS
CountryJapan
CityKyoto
Period14/09/1816/09/18
Internet address

Keywords

  • HGSOC
  • IBET
  • BRD4
  • ATAC-sequencing

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