Abstract 3781
Background
Metastatic ovarian and basal-like breast cancers are incurable diseases with limited therapeutic options. In our study, we explored synergistic interactions of Chk1 inhibitors (rabusertib and SAR020106) with approved therapies in these indications. In addition, we evaluated the role of these agents to overcome platinum resistance.
Methods
We evaluate the effect of rabusertib and chemotherapic agents in ovarian (OVCAR3, OVCAR8, IGROV1, SKOV3) and breast (MDA-MB-231, HS578T, BT549, HCC3153) cancer cell lines. We also use the commercially available cell line A2780Rcis and a breast cancer model created in our laboratory, MDA-MB231Rcis.
Results
The combination of platinum agents, cisplatin and carboplatin was synergistic with Chk1 inhibitors rabusertib and SAR020106 in most of basal-like and ovarian cancer cell lines. The combination of rabusertib with gemcitabine was very synergistic in basal-like cell lines but not in ovarian cancer. Doxorubicin, another DNA damaging agent, was also synergistic in ovarian cell lines, but showed less activity in the breast models. Combinations with topotecan were slightly synergistic only in basal-like tumors. The combination of rabusertib with agents that target mitosis were not synergistic. The combination of Chk1 inhibitor with platinum compounds or gemcitabine affects colony formation and tumor invasiveness. Combination of platinum agents and gemcitabine with rabusertib induced cell death that was mainly mediated by caspases. The effect of rabusertib on platinum resistance showed addition of Chk1 inhibitor to cisplatin induces cell death in cisplatin resistant cells.
Conclusions
Inhibition of Chk1 has a strong synergistic interaction with DNA damaging agents, including platinum compounds, gemcitabine and olaparib, on both tumor types. The effect of rabusertib with platinum agents and gemcitabine on colony growth and long-term effect confirms the effect on proliferation, invasion and long-term survival in basal-like and ovarian cancer cell lines. Addition of rabusertib to cisplatin induces cell death in all the cell lines including the resistant cells, demonstrate that resistance to cisplatin can be overcome by inhibition of Chk1 kinase.
Clinical trial identification
NA
Editorial acknowledgement
NA
Legal entity responsible for the study
Alberto Ocaña.
Funding
Instituto de Salud Carlos III (PI16/01121) Diputación de Albacete and CIBERONC CRIS Cancer Foundation cancer association ACEPAIN research program of the UCLM regional fellowship for Biomedicine and Health science research (II-2018_11).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
1122 - Platelets from metastatic cancer patients have increased aggregation and activation
Presenter: Meera Chauhan
Session: Poster Display session 3
Resources:
Abstract
2671 - Luminal B breast cancer prognosis prediction by comprehensive analysis of Homeobox genes
Presenter: Ayako Nakashoji
Session: Poster Display session 3
Resources:
Abstract
2650 - Long non-coding RNA E2F4as promotes tumor progression and predicts patient prognosis in human ovarian cancer
Presenter: Sun-Ae Park
Session: Poster Display session 3
Resources:
Abstract
1462 - FGF19 promotes esophageal squamous cell carcinoma progression by inhibiting autophagy
Presenter: Lisha Ying
Session: Poster Display session 3
Resources:
Abstract
5787 - Proof of concept on the role of ex vivo lung cancer spheroids, cytokines expression and PBMCs profiling in monitoring disease history and response to treatments.
Presenter: Raimondo Di Liello
Session: Poster Display session 3
Resources:
Abstract
5253 - Circulating microRNAs related to DNA damage response as predictors of survival in metastatic non- small cell lung cancer patients treated with platinum-based chemotherapy
Presenter: Dimitris Mavroudis
Session: Poster Display session 3
Resources:
Abstract
5286 - Prognostic value of CTCs in advanced NSCLC patients treated with platinum-based chemotherapy
Presenter: Silvia Calabuig-Fariñas
Session: Poster Display session 3
Resources:
Abstract
5781 - Exosomes in NSCLC as a source of biomarkers
Presenter: Elena Duréndez
Session: Poster Display session 3
Resources:
Abstract
1447 - The role of Pim-1 in the development and progression of papillary thyroid carcinoma
Presenter: Xin Zhu
Session: Poster Display session 3
Resources:
Abstract
1323 - Development and Validation of a RNA-Seq Based Prognostic Signature in Neuroblastoma
Presenter: Jian-Guo Zhou
Session: Poster Display session 3
Resources:
Abstract