Abstract 583P
Background
Despite benefit of PARP inhibitors (PARPi) in high grade ovarian cancer (HGOC) a proportion of patients will become resistant. The aim of our study was to assess if AURKA overexpression is a mechanism of PARPi resistant and if the inhibition with alisertib (ALI) could overcome resistance to olaparib (OLA) in cell line models.
Methods
AURKA expression in tumor samples from 39 patients (19 BRCA mut and 20 BRCA wt) from 3 institutions before (N=39) and after (N=16) progression to PARPi were assessed for AURKA expression (14 paired biopsies). HGOC OLA-sensitive cell lines PEO1 and Kuramochi (KURA) were acquired. PEO1 resistant to OLA (PEO1-R) was generated by pulse method. Cells were exposed for 24 hours to the PEO1 IC75 OLA. IC50 of OLA and ALI and the combination of both (combo) were calculated for KURA, PEO1 and PEO1-R cell lines. Synergism between both drugs was assessed with the Chou Talalay method for combination index (CI) at Fa50.
Results
A non-significant AURKA overexpression was seen in PARPi resistant samples (39 pre vs 16 post-progression) (p=0.069). 3 paired BRCA2 and 2 out of 3 BRCA1-mutant pairs increased AURKA expression. BRCA wt paired-samples were non-consistent. In our BRCA2 mutant In vitro models AURKA by WB was also overexpressd in PEO1-R vs PEO1.Addition of ALI to OLA (combo) significantly decreased the OLA IC50 vs OLA (KURA 15.4uM OLA vs 6.1 combo p=0.018, and PEO1 21.33 uM OLA vs 9.58 combo p<0.0001) and increased gamma-H2AX expression in OLA-sensitive cells. PEO1-R resistance was confirmed (OLA IC50 3.2 PEO1 vs 32.35uM PEO1-R p<0.0001). In PEO1-R addition of ALI also decreased significantly OLA IC50 (43.6 for OLA vs 10.28uM for combo, p<0.0001). CI showed a synergistic effect for the combo in all cell lines: Kuramochi CI: 0.33, PEO1 0.76 and PEO1R 0.37. This effect was higher in PEO1-R (IC50 OLA single agent 42.18 uM vs 4.76 uM with combo) than in PEO1 (IC50 OLA 19.54 uM vs 4.44 uM with combo) suggesting that ALI might overcoming OLA-resistance.
Conclusions
Inhibition of AURKA by adding ALI to OLA has a synergistic effect and overcomes OLA resistance in vitro. AURKA overexpression seems to be relevant in resistance to PARPi.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Mutua Madrileña and SEOM grants.
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. Romeo Marin: Financial Interests, Personal, Expert Testimony, Educational purposes: MSD; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Institutional, Invited Speaker: Tesaro, MSD, Roche, IMNG. 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. M. Gil Martín: Financial Interests, Personal, Invited Speaker: MSD, GSK, Clovis. O. Burgués: Financial Interests, Personal, Invited Speaker: Roche, MSD. A. Cervantes: Financial Interests, Institutional, Advisory Board: MerckSerono, Amgen, Roche, Transgene, AnHeart Therapeutics; Financial Interests, Institutional, Invited Speaker: Amgen, Roche, Merck Serono, Foundation Medicine; Financial Interests, Personal, Other, Associate Editor: Annals of Oncology, ESMO Open; Financial Interests, Personal, Other, Editor: Cancer Treatment Reviews; Financial Interests, Institutional, Research Grant, Principal Investigator: Actuate Therapeutic, Amgen, Astellas Pharma, Beigene, Bayer, AstraZeneca, BMS, Amcure, FibroGen, Lilly, Genentech, MedImmune, Merck Serono, Novartis, Natera, MSD, Servier, Sierra Oncology, Adaptimmune, Takeda; Non-Financial Interests, Other, General and Scientific Director: INCLIVA Biomedical Research Institute. All other authors have declared no conflicts of interest.