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
2262 - Real world experience of Nivolumab therapy in Metastatic Renal Cancer patients: a 3 year multi-centre review
Presenter: Joanna Hack
Session: Poster Display session 3
Resources:
Abstract
4441 - “A pilot study of tremelimumab (treme) with or without cryoablation (cryo) in patients (pts) in metastatic renal cell carcinoma (mRCC).”
Presenter: Matthew Campbell
Session: Poster Display session 3
Resources:
Abstract
2613 - Lenvatinib (Len) alone or in combination with Everolimus (Eve) in heavily pretreated patients (pts) with metastatic renal cell carcinoma (mRCC) after immune checkpoint inhibitors (ICI) and VEGFR-targeted therapies: A single-institution experience
Presenter: Andrew Wiele
Session: Poster Display session 3
Resources:
Abstract
3249 - Weight loss is an underestimated adverse event with cabozantinib in patients with metastastic renal cell carcinoma (mRCC).
Presenter: Emeline Colomba
Session: Poster Display session 3
Resources:
Abstract
2405 - Impact of corticosteroids on nivolumab activity in metastatic clear cell renal cell carcinoma.
Presenter: Felix Lefort
Session: Poster Display session 3
Resources:
Abstract
4020 - Skeletal muscle loss as an adverse event during Cabozantinib treatment in patients with metastatic renal cell carcinoma
Presenter: Carolina Alves Costa Silva
Session: Poster Display session 3
Resources:
Abstract
2407 - Long term relative survival (RS) in patients with primary metastatic kidney cancer (primary mRCC): an analysis of 2,167 patients from the Austrian National Cancer Registry (ANCR).
Presenter: Monika Hackl
Session: Poster Display session 3
Resources:
Abstract
2470 - Advanced renal cell carcinoma: first results from the prospective research platform CARAT for patients with mRCC in Germany
Presenter: Peter Goebell
Session: Poster Display session 3
Resources:
Abstract
1533 - Are immune checkpoint inhibitors a valid option for papillary Renal Cell Carcinoma? Transcriptomic characterization of the immune infiltrate
Presenter: Manon De Vries-brilland
Session: Poster Display session 3
Resources:
Abstract
3367 - Treatment-Free Survival, With and Without Toxicity, as a Novel Outcome Applied to Immuno-Oncology Agents in Advanced Renal Cell Carcinoma
Presenter: Meredith Regan
Session: Poster Display session 3
Resources:
Abstract