Abstract 8P
Background
Low-grade serous ovarian carcinoma (LGSC) is a rare subtype with distinctive genomic characteristics and low response to platinum chemotherapy. Outcomes for advanced LGSC are poor, therefore treatment options, including non-platinum chemotherapy need to be explored. Importantly, predictive biomarkers are needed to avoid exposure to toxic ineffective treatments. We aimed to identify molecular features predictive of response to docetaxel, paclitaxel and gemcitabine in well-defined LGSC cell line models.
Methods
Cell viability was assessed following docetaxel, paclitaxel and gemcitabine exposure in eight LGSC lines (CellTiter 96™ MTS Assay, Promega). RNA was sequenced (RNAseq, Illumina HiSeq2000) and analysed using EdgeR & clusterProfiler.
Results
The LGSC cell lines had MAPK pathway variants that are reflective of clinical samples (Table). HOC7 was relatively sensitive to all three agents. MPSC1 was sensitive to docetaxel and gemcitabine, and HO433 was only sensitive to gemcitabine. WMINV10, WMOV24 and WMINV13 were relatively resistant to all agents. There was no association between RAS/RAF mutation and drug response.Table: 8P
IC50 (nM) of LGSC cell lines, ordered by docetaxel IC50
| Cell Line | RAS/RAF Mutation | Docetaxel IC50 | Paclitaxel IC50 | Gemcitabine IC50 |
| MPSC1 | BRAFV600L, NRASQ61R | 1.8 | 6.1 | 10 |
| HCC5075 | KRASG12V | 2 | 1.5 | 18 |
| HOC7 | KRASG12A | 2.1 | 1.7 | 5 |
| AOCS2 | WT | 6.6 | 11.4 | 29 |
| WMINV10 | KRASG12V | 38.2 | NR | 1669 |
| WMOV24 | KRASG12D | 95 | NR | 1038 |
| HO433 | WT | 103 | 113.8 | 5.1 |
| WMINV13 | NRASQ61R | NR | NR | 3451 |
WT = wild type; NR= not reached.
Transcriptome analysis showed epithelial to mesenchymal transition genes to be strongly associated with resistance to docetaxel (Gene Set Enrichment Analysis, GSEA q=2.1x10-10) and paclitaxel (GSEA q=1.1x10-10) whereas pathways involving DNA replication were upregulated in cell lines sensitive to docetaxel (p-adj=0.0004). Neuronal system pathways were upregulated in cell lines resistant to gemcitabine (p-adj=9.4x10-11) and docetaxel (p-adj=2.8x10-12).
Conclusions
Our pre-clinical data suggests that non-platinum chemotherapy may be a viable option in selected LGSC patients. Gene expression profiles associated with response to specific agents were identified. However, these findings need further validation in patient samples.
Legal entity responsible for the study
The authors.
Funding
Westmead Charitable Trust ECR Medical Clinician-Researcher Grant 2021, Cancer Council NSW (RG-15-23) and Cancer Australia (APP1142697). The INOVATe study has received funding from the Cancer Institute NSW (14/TPG/1-15), the Cancer Council NSW (TPG 20-01) and the University of Sydney. AOCS was supported by the U.S. Army Medical Research and Material Command under DAMD17-01-1-0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Foundation of Western Australia, The Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; ID400413, ID400281). The Gynaecological Oncology Biobank at Westmead was funded by the NHMRC (ID310670, ID628903); the Cancer Institute NSW (12/RIG/1-17, 15/RIG/1-16); and acknowledges support from the Department of Gynaecological Oncology, Westmead Hospital and the Sydney West Translational Cancer Research Centre (Cancer Institute NSW 15/TRC/1-01). Dr Seema Kumari was the recipient of a PhD Scholarship from Sydney Cancer Partners with funding from Cancer Institute NSW (2021/CBG0002).
Disclosure
T. Moujaber: Financial Interests, Personal, Advisory Board: Merck/Pfizer, BMS; Financial Interests, Personal, Invited Speaker, Education webinar/Speaker honoraria: Amgen, Eisai. N. Traficante: Financial Interests, Institutional, Research Grant: AstraZeneca. C. Gourley: Financial Interests, Personal, Invited Speaker, Both personal and institutional: Roche, AstraZeneca, MSD, GSK, Clovis, Chugai, Takeda, Eisai; Financial Interests, Personal, Advisory Board, Both personal and institutional: AstraZeneca, MSD, GSK; Financial Interests, Personal, Invited Speaker: Cor2Ed, PeerVoice; Financial Interests, Personal, Other, IDMC: MSD; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Aprea, Nucana, Medannex; Financial Interests, Institutional, Invited Speaker: GSK, BerGenBio, MSD, Clovis, Roche, Verastem; Non-Financial Interests, Personal, Other, Committee member: Cancer Research UK Clinical Research Committee; Non-Financial Interests, Personal, Other, Committee Member: German Cancer Aid Scientific Review Committee, International Clinical Cancer Research Committee, Institut National du Cancer, France. D. Bowtell: Financial Interests, Personal, Other, Personal consulting fees (that are outside the submitted work): Exo Therapeutics; Financial Interests, Institutional, Other, Patent application to be submitted (unrelated to the submitted work).: Henry Jackson Foundation INOVA HealthCare University of Melbourne; Financial Interests, Institutional, Funding, Research support paid to my institution.: Roche/Genentech, AstraZeneca, BeiGene. A. Defazio: Financial Interests, Institutional, Other, Donation as compensation for time commitment to the International Consortium for Low-Grade Serous Ovarian Cancer: Ludemann Family; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Other, Research collaboration - services provided: Illumina. All other authors have declared no conflicts of interest.