Abstract Number: 4821
Presentation Title: The WEE1 inhibitor AZD-1775 has synergic activity with trabectedin or lurbinectedin in ovarian cancer cells .
Presentation Time: Wednesday, Apr 20, 2016, 7:30 AM -11:00 AM
Author Block: Sarah Uboldi, Laura Carrassa, Roberta Frapolli, Paolo Ubezio, Eugenio Erba, Maurizio D'Incalci. IRCCS Istituto di Ricerche Farmacologiche Mario Negri - Milano, Milan, Italy .
Abstract Body: AZD-1775 is a small molecule that selectively inhibits the tyrosine kinase WEE1, with a reported antineoplastic activity in ovarian cancer. WEE1 is a tyrosine kinase key regulator of DNA damage surveillance pathways that controls G2/M transition and ensures faithful DNA replication. WEE1 is required during normal S phase to avoid deleterious DNA breakage and prevent loss of genome integrity in the absence of exogenous DNA damage.
Trabectedin is a drug approved in 2007 by EMA and 2015 by FDA for the treatment of soft tissue sarcomas and in 2009 by EMA for the treatment of ovarian cancer patients, who have relapsed after 6 months from Platinum-based therapy, in combination with pegylated liposomal doxorubicin.
Lurbinectedin (PM01183) is a trabectedin analog with a similar mechanism of action and, according to ongoing clinical investigations, less toxic and thus suitable for combinations of potential clinical interest.
Since both trabectedin and lurbinectedin cause a G2/M block and AZD-1775 is able to inhibit the WEE1 activity with consequent disruption of G2/M checkpoint, we hypothesized that the combined treatment with AZD-1775 could be synergistic in ovarian cancer cells.
The sensitivity of the ovarian cancer cell lines OVCAR-5, A2780 and IGROV-1 to trabectedin, lurbinectedin and AZD-1775 alone or in combination (72h of continous treatment) was evaluated by a cell proliferation assay. The cytotoxic effect induced by the simultaneous administration of trabectedin with AZD-1775 or lurbinectedin with AZD-1775 was evaluated by a combination index analysis.t
The results obtained showed that the combination trabectedin with AZD-1775 or lurbinectedin with AZD-1775 is synergic in all the ovarian cancer cell lines analyzed Combination Index
If the synergism observed in vitro will be confirmed in vivo, there will be a strong rationale to test these combinations in ovarian cancer patients.