Abstract 585P
Background
Retrospective evidence suggests that patients with high grade ovarian cancer (HGOC) progressing to PARP inhibitors (PARPi) might be less likely to response to platinum therapy. The aim of our study was to assess in preclinical models if trabectedin will be an active agent in carboplatin-and PARPi-resistant HGOC cell lines.
Methods
HGOC Olaparib (OLA)/Carboplatin (carbo)-sensitive BRCA2 mutant p.Y1655* cell line PEO1, and carbo-resistant cell line PEO4 were acquired. PEO1 resistant to OLA (PEO1-R) cell line was generated by pulse method. Cells were exposed for 24 hours to the PEO1 IC75 OLA and recovered for two weeks. Pulses were repeated during a 6-month period. IC50 of OLA, carbo and trabectedin were calculated for PEO1, PEO4 and PEO1-R cell lines. DNA damage was assessed by gamma-H2AX expression by western-blot (WB). BRCA and TP53 mutations were explored by NGS.
Results
NGS confirmed that reversion of BRCA2 mutation was present in PEO4 but not in the PEO1-R cell line in which BRCA2 mutation p.Y1655* was detectable. TP53 mutations were invariable. We confirmed that PEO4 was platinum-resistant vs PEO1 parental line (IC50 for carbo 63.54uM vs 99.1uM; p<0.0001). Moreover PEO4 showed a cross-resistance to OLA (IC50 5.65 nM PEO1 vs 55.70 nM PEO4; p<0.0001). PEO1-R cell line was resistant to OLA compared with parental PEO1 (3.18 nM for PEO1 vs 48.31 nM PEO1R; p<0.0001) and PEO1-R showed a cross-resistance to carbo (42.47nM PEO1 s 71.05nM for PEO1R; p< 0.0001). In a second step we assessed if trabectedin could be a potential agent to overcome carbo or OLA resistance in cell lines. PEO4 carbo-resistant cell line was also resistant to trabectedin (trabectedin IC50 PEO1 378.7 nM vs PEO4 1231 nM; p=0.0021). However, OLA resistant PEO1-R cell line showed similar values for trabectedin IC50 compared to PEO1 (454nM vs 397nM for PEO1R; p=0.645). Increased gamma-H2AX expression in WB vs control was seen in all three lines PEO1, PEO1-R and PEO4 when treated with trabectedin.
Conclusions
This preclinical in vitro model suggests that some HGOC cell lines resistant to PARPi could potentially be still sensitive to trabectedin.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
PharmaMar.
Disclosure
J.A. Perez Fidalgo: Financial Interests, Personal, Invited Speaker: AstraZeneca, Clovis, GSK, PharmaMar, AstraZeneca, Mersana Therapeutics; Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, Clovis, PharmaMar, Roche, Abilify Pharma; Financial Interests, Personal, Expert Testimony: Samsung Pharmaceutics; Financial Interests, Personal, Full or part-time Employment, Associate Professor: University of Valencia; Financial Interests, Institutional, Research Grant: GSK, PharmaMar; Financial Interests, Institutional, Invited Speaker: Novartis, AstraZeneca; Financial Interests, Institutional, Funding: GSK; Non-Financial Interests, Project Lead, Coordinating PI Phase III trial in breast cancer: Novartis; Non-Financial Interests, Member, Member of the Early Drug Development working group: ENGOT; Non-Financial Interests, Leadership Role, Head of the Scientific Committee of GEICO: GEICO; Non-Financial Interests, Member, Member of the Uterine Sarcoma Group: GEIS; Non-Financial Interests, Member: GCIG, BIG. M. Mendiola: Financial Interests, Personal, Other, Honoraria: MSD, AZD, GSK; Financial Interests, Institutional, Research Grant: Eisai, PharmaMar. A. Redondo Sanchez: Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, GSK, Clovis, PharmaMar; Financial Interests, Personal, Advisory Board: MSD, AstraZeneca, GSK, Clovis, PharmaMar; Financial Interests, Institutional, Invited Speaker: Roche, Eisai, PharmaMar. O. Burgués: Financial Interests, Personal, Invited Speaker: Roche, MSD. All other authors have declared no conflicts of interest.