Abstract 125P
Background
High-grade serous ovarian cancer (HGSOC) is the most lethal histologic subtype of ovarian cancer and even though therapies have improved significantly over the last years, survival rates remain low. Thus, improvements for treating patients suffering from this disease are urgently needed.1 Combination of already available drugs aims to enhance treatment response in cancer patients by employing their synergistic interactions.2 This project aimed to investigate effects of a combined targeting of cell proliferation and apoptosis in HGSOC.
Methods
Four HGSOC cell lines were exposed to the PIK3CA inhibitor alpelisib, pan-MEK inhibitor trametinib and BH3-mimetic navitoclax at 10, 5, 2.5 and 1.25 μM each. Alpelisib and trametinib were each combined with navitoclax. Cells were seeded in 96 well plates and left to attach to the surface for 24 h before drug exposure. Viability was assessed after 72 h using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega). Experiments were repeated independently three times and analyses were performed in R. Findings were evaluated as significant if p ≤ 0.05.
Results
Taken together initial outcomes indicate synergistic interactions of navitoclax with alpelisib and trametinib. Drug combinations enhanced inhibition of cell viability when compared to single agent treatment. Overall, navitoclax and trametinib impaired viability more than the combination of navitoclax with alpelisib, resulting in a higher combination sensitivity score (CSS). Even though no combination statistically outperformed treatment with 10 μM navitoclax, combinations significantly reduced viability when compared to the highest concentration of alpelisib and trametinib. The lowest concentration to significantly reduce viability in combination screens was 5 μM of each drug.
Conclusions
These first results confirm that targeting proliferation and apoptosis synergistically impair cell viability in HGSOC and might therefore be interesting targets to induce synthetic lethality. Based on these screening results further investigations will focus on induction of apoptosis and the underlying molecular mechanisms. Furthermore, these results will be validated in a 3D model using HGSOC organoids.
Editorial acknowledgement
Clinical trial identification
Legal entity responsible for the study
L. Wozelka-Oltjan.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
136P - Molecular correlates of drug response to guide therapy in TNBC
Presenter: Nathan Merrill
Session: Cocktail & Poster Display session
Resources:
Abstract
137P - Event-free survival prediction using lncRNAs in pediatric B-cell acute lymphoblastic leukemia
Presenter: Unai Illarregi
Session: Cocktail & Poster Display session
Resources:
Abstract
138P - Exome sequencing analysis for the identification of actionable mutations related to neoadjuvant chemotherapy response in locally advanced breast cancer
Presenter: Ximena López
Session: Cocktail & Poster Display session
Resources:
Abstract
139P - Genomic prognostic and potential theragnostic factors in anal squamous cell carcinoma treated with abdominoperineal resection
Presenter: Abderaouf Hamza
Session: Cocktail & Poster Display session
Resources:
Abstract
144P - Correlation of EZH2 expression and response to chemoradiotherapy in patients with locally advanced inoperable oral cavity and oropharyngeal squamous cell cancers
Presenter: Soel Ahmed
Session: Cocktail & Poster Display session
Resources:
Abstract
140P - Predictive value of DNA damage response and repair gene alterations and neoscore for neoadjuvant immunotherapies in non-small cell lung cancer
Presenter: Fei Feng
Session: Cocktail & Poster Display session
Resources:
Abstract
141P - Immune-related epigenomic and transcriptomic signatures to predict immunotherapy response in NSCLC
Presenter: María Gallardo-Gómez
Session: Cocktail & Poster Display session
Resources:
Abstract
142P - Role and impact of hypoxia-inducible factor 1-alpha on survival rates in pancreatic cancer: A systematic review and meta-analysis
Presenter: Muhammed Elfaituri
Session: Cocktail & Poster Display session
Resources:
Abstract
143P - Genomic characterization and outcomes of patients with primary sclerosing cholangitis-related cholangiocarcinoma
Presenter: Jaime Haro Silerio
Session: Cocktail & Poster Display session
Resources:
Abstract
145P - Identification of next generation sequencing (NGS)-based genomic signature predicting resistance to immunotherapy (IO) in patients (pts) with metastatic non-small cell lung cancer (mNSCLC): A single-center cohort study
Presenter: Antonio Vitale
Session: Cocktail & Poster Display session
Resources:
Abstract