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. 2024 Jul:186:42-52.
doi: 10.1016/j.ygyno.2024.03.029. Epub 2024 Apr 5.

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

Robert L Hollis  1 , Richard Elliott  2 , John C Dawson  2 , Narthana Ilenkovan  3 , Rosie M Matthews  4 , Lorna J Stillie  3 , Ailsa J Oswald  4 , Hannah Kim  5 , Marta Llaurado Fernandez  5 , Michael Churchman  4 , Joanna M Porter  4 , Patricia Roxburgh  6 , Asier Unciti-Broceta  2 , David M Gershenson  7 , C Simon Herrington  4 , Mark S Carey  5 , Neil O Carragher  2 , Charlie Gourley  4
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Free article

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

Robert L Hollis et al. Gynecol Oncol. 2024 Jul.
Free article

Abstract

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.

Keywords: Cancer therapy; Dasatinib; Disulfiram; Drug repurposing; High throughput screen; Low grade serous ovarian carcinoma; Ovarian cancer; Src family kinases.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RLH: consultancy fees from GlaxoSmithKline and DeciBio. RE: none. JCD: none. NI: none. RM: none. LJS: none. AJO: research funding from AstraZeneca (jointly funded Clinical Research Training Fellowship with Cancer Research UK) outside the scope of this work. HK: none. MLF: none. MC: none. JMP: none. PR: translational research grants from GSK, Atrios; funds to institution for clinical trials delivery from AstraZeneca, Atrios, Clovis, Forma, GSK, Tesaro, Imuntep, Incyte, Iovance, Mersana, Nucana, PsiOxus, Replimune, Sierra, Starpharma; personal fees from AstraZeneca, GSK, Starpharma. AUB: patents (EP3298015B1, JP6684831B2, US10294227B2, CN107849050B, CA3021550A1) pertaining to the discovery of eCF506/NXP900 that have been licensed to Nuvectis Pharma Inc.; research grants from Nuvectis Pharma. DG: grant from Novartis; consultancy fees from Verastem; royalties from Elsevier, UpToDate; personal fees for Advisory Boards from Verastem, Aadi, Beigene/Springworks, Onconova; stock equity in Johnson & Johnson, Bristol Myers Squibb, Procter and Gamble, all outside the scope of this work. CSH: none. MSC: grants from Ovarian Cancer Canada; consulting fees from Verastem. NOC: patents (EP3298015B1, JP6684831B2, US10294227B2, CN107849050B, CA3021550A1) pertaining to the discovery of eCF506/NXP900 that have been licensed to Nuvectis Pharma Inc.; research grants from Nuvectis Pharma. CG: grants from AstraZeneca, MSD, BMS, GSK, Clovis, Novartis, BerGenBio, Medannex, Roche, Verastem, Artios; personal fees from AstraZeneca, MSD, GSK, Clovis, Verastem, Eisai, Roche, Takeda, Peervoice and Cor2Ed outside the scope of this work.

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