Browsing Over 107 Presentations
Welcome to the ESMO Gynaecological Cancers Congress 2022
- The Panelists (Valencia, Spain)
Live Q&A
- Carien L. Creutzberg (Leiden, Netherlands)
Recent developments in adjuvant treatment
- Carien L. Creutzberg (Leiden, Netherlands)
Introduction
- Mansoor Raza Mirza (Copenhagen, Denmark)
New treatment options for advanced and metastatic disease
- Alexandra Leary (Villejuif, France)
Recent developments in surgery for early-stage disease
- Christian Marth (Innsbruck, Austria)
Live Q&A
- Bradley J. Monk (Phoenix, AZ, United States of America)
Digging into molecular characterization of high-grade ovarian cancer: BRCA, HRD and beyond
- Nicole Concin (Innsbruck, Austria)
Should we really use PD-L1 as a selection driver in cervical cancer?
- Bradley J. Monk (Phoenix, AZ, United States of America)
The role of MAPK pathway to select therapy in low-grade ovarian cancer
- Susana Banerjee (London, United Kingdom)
MMR status, TMB or both: How to identify endometrial cancer patients who benefit the most from immunotherapy
- Vicky Makker (New York City, NY, United States of America)
1P - Comprehensive assessment of gene mutations revealed overlapping responses for PARPi and chemotherapy in ovarian cancer cells
- Alessandra Tozzi (Basel, Switzerland)
Abstract
Background
PARP inhibitors (PARPi) have revolutionized the therapeutic landscape of epithelial ovarian cancer (EOC) treatment, showing outstanding benefits in regards to progression-free survival, especially in patients carrying BRCA1/2 mutations or harboring defects in homologous recombination repair. Yet, it remains uncertain which PARPi to choose and how to select responders by using clinical and molecular characteristics, especially in forefront therapy when platinum sensitivity is unknown.
Methods
Through a systematic literature review and the exploration of publicly available CRISPR-Cas9 library screens and Genomics of Drug Sensitivity in Cancer data, we identified potential genes linked with PARPi response. Using a CRISPR-Cas9 mutagenesis assay, we functionally tested 33 genes for PARPi and carboplatin response in six ovarian cancer (OC) cells lines.
Results
ATM was the only tested gene which induced olaparib sensitivity in a cell line-independent manner. Acquired olaparib sensitivity was also observed upon Cas9-mediated loss of MUS81, NBN, RAD51/B/C, RNASEH2A, PALB2, XRCC1, and XRCC3 in at least 3 out of 6 cell lines. As the major survival benefit of PARPi treatment was reported in chemo-sensitive tumors, we next assessed the effect of top candidate genes on olaparib, niraparib, talazoparib, and carboplatin response. Interestingly, we observed identical effects in a gene- and drug compound-independent manner on acquired drug sensitivity, supporting the strong correlation of cancer cell response to PARPi and chemotherapy. In contrast, we identified CDK12 as an essential gene for cell proliferation/survival in ovarian cancer cells, independent of PARPi and chemotherapy treatment.
Conclusions
Our data suggest a general mechanism of response to PARPi and chemotherapy as demonstrated by various overlapping gene dependencies. The screen of the genetic status of the genes identified correlated with PARPi sensitivity may allow better stratification of patients with increased benefit to this treatment.
Legal entity responsible for the study
The authors.
Funding
Swiss National Science Foundation (CRSII5_171037), Griesbach-Hallenstein Foundation (Walter Edwin Griesbach Award and Olga Hallenstein Award), Department of Biomedicine, University Hospital Basel and University of Basel.
Disclosure
All authors have declared no conflicts of interest.