High throughput screening identifies dasatinib as synergistic with trametinib in low grade serous ovarian carcinoma

Robb Hollis*, Richard Elliott, John C Dawson, Narthana Ilenkovan, Rosie Matthews, Lorna Stillie, Ailsa Oswald, Hannah Kim, Marta Llaurado Fernandez, Michael Churchman, Joanna C Porter, Patricia Roxburgh, Asier Unciti-Broceta, David M Gershenson, C Simon Herrington, Mark S Carey, Neil O Carragher, Charlie Gourley

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Background

Low grade serous ovarian carcinoma (LGSOC) is a distinct histotype of ovarian cancer characterised high levels of intrinsic chemoresistance, highlighting the urgent need for new treatments. High throughput screening in clinically-informative cell-based models represents an attractive strategy for identifying candidate treatment options for prioritisation in clinical studies.

Methods

We performed a high throughput drug screen of 1610 agents across a panel of 6 LGSOC cell lines (3 RAS/RAF-mutant, 3 RAS/RAF-wildtype) to identify novel candidate therapeutic approaches. Validation comprised dose-response analysis across 9 LGSOC models and 5 high grade serous comparator lines.

Results

16 hits of 1610 screened compounds were prioritised for validation based on >50% reduction in nuclei counts in over half of screened cell lines at 1000 nM concentration. 11 compounds passed validation, and the four agents of greatest interest (dasatinib, tyrosine kinase inhibitor; disulfiram, aldehyde dehydrogenase inhibitor; carfilzomib, proteasome inhibitor; romidepsin, histone deacetylase inhibitor) underwent synergy profiling with the recently approved MEK inhibitor trametinib. Disulfiram demonstrated excellent selectivity for LGSOC versus high grade serous ovarian carcinoma comparator lines (P = 0.003 for IC50 comparison), while the tyrosine kinase inhibitor dasatinib demonstrated favourable synergy with trametinib across multiple LGSOC models (maximum zero interaction potency synergy score 46.9). The novel, highly selective Src family kinase (SFK) inhibitor NXP900 demonstrated a similar trametinib synergy profile to dasatinib, suggesting that SFK inhibition is the likely driver of synergy.
Conclusion

Dasatinib and other SFK inhibitors represent novel candidate treatments for LGSOC and demonstrate synergy with trametinib. Disulfiram represents an additional treatment strategy worthy of investigation.
Original languageEnglish
JournalGynecologic Oncology
DOIs
Publication statusPublished - 5 Apr 2024

Keywords / Materials (for Non-textual outputs)

  • low grade serous ovarian carcinoma
  • carcinoma
  • ovarian cancer
  • high throughput screen
  • cancer therapy
  • dasatinib
  • disulfiram
  • Src family kinases
  • drug repurposing

Fingerprint

Dive into the research topics of 'High throughput screening identifies dasatinib as synergistic with trametinib in low grade serous ovarian carcinoma'. Together they form a unique fingerprint.

Cite this