American Association for Cancer Research
15357163mct170223-sup-180240_2_supp_4184672_ctr3rp.ppt (1.29 MB)

Figure S4 from Synthetic Lethality Interaction Between Aurora Kinases and CHEK1 Inhibitors in Ovarian Cancer

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posted on 2023-04-03, 15:50 authored by Ana Alcaraz-Sanabria, Cristina Nieto-Jiménez, Verónica Corrales-Sánchez, Leticia Serrano-Oviedo, Fernando Andrés-Pretel, Juan Carlos Montero, Miguel Burgos, Juan Llopis, Eva María Galán-Moya, Atanasio Pandiella, Alberto Ocaña

Fluorescence imaging of aberrant mitotic formation and caspase-3 activity in response to Alisertib and LY2603618 in ovarian cell lines


Institute of Health Carlos III

Ministry of Economy and Competitiveness of Spain

Miguel Servet

Pasteur Institute-Cenci Bolognetti Foundation



Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair genes, so they rely on DNA-damage checkpoint proteins, like the checkpoint kinase 1 (CHEK1) to induce G2 arrest. In our study, by using an in silico approach, we identified a synthetic lethality interaction between CHEK1 and mitotic aurora kinase A (AURKA) inhibitors. Gene expression analyses were used for the identification of relevant biological functions. OVCAR3, OVCAR8, IGROV1, and SKOV3 were used for proliferation studies. Alisertib was tested as AURKA inhibitor and LY2603618 as CHEK1 inhibitor. Analyses of cell cycle and intracellular mediators were performed by flow cytometry and Western blot analysis. Impact on stem cell properties was evaluated by flow cytometry analysis of surface markers and sphere formation assays. Gene expression analyses followed by functional annotation identified a series of deregulated genes that belonged to cell cycle, including AURKA/B, TTK kinase, and CHEK1. AURKA and CHEK1 were amplified in 8.7% and 3.9% of ovarian cancers, respectively. AURKA and CHEK1 inhibitors showed a synergistic interaction in different cellular models. Combination of alisertib and LY2603618 triggered apoptosis, reduced the stem cell population, and increased the effect of taxanes and platinum compounds. Finally, expression of AURKA and CHEK1 was linked with detrimental outcome in patients. Our data describe a synthetic lethality interaction between CHEK1 and AURKA inhibitors with potential translation to the clinical setting. Mol Cancer Ther; 16(11); 2552–62. ©2017 AACR.

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