Abstract 5818
Background
Somatic mutation in TP53 gene (mutp53) is a strong prognostic marker in breast cancer. Triple negative breast cancer (TNBC) is characterized by up to 80% mutp53 and the greatest overall genomic instability among subtypes. Polo-like kinase 1 (PLK1) regulates progression of cells through the G2 phase of the cell cycle. We hypothesize that mutp53 in the context of breast cancer can predict synergy to paclitaxel [p] plus onvansertib [o], an orally available highly selective Plk1 inhibitor.
Methods
Drugs were tested in a set of mutp53 breast cancer cells including TNBC SUM149 and SUM159, luminal SUM52 and T47D, and wtp53 TNBC SUM1315, luminal MCF7, and normal breast MCF10A. We performed cell proliferation assays in order to determine the IC50 (Inhibition Concentration of 50%) for each drug. Synergism was determined using the Chou-Talalay method, by determining the combination index (CI). Apoptosis was determined by PARP cleavage proteins detection in cells synchronized with double thymidine block. For the in vivo experiments, mice were injected with 5x106 SUM159 cells and randomly assigned to experimental condition (control, o, p, o+p). The primary endpoint was tumor volume (TV) measured longitudinally. We performed one-sided two-samples Wilcoxon test comparing the means of the adjusted TV measured at 10 days for p and o+p.
Results
TNBC cells were more sensitive to single agent o compared to luminal cells. Breast cell lines with mutp53 (SUM149, SUM159, SUM52 and T47D) were found to have Combination Index (CI) < 1 when treated with o+p. Conversely, in cell line with wtp53 (SUM1315, MCF7, and MCF10A), o+p did not show synergy, CI ≥ 1. Western blot showed prolonged apoptosis for PLK1 inhibition plus taxane compared to PLK1 inhibitor alone, in SUM149 and SUM159. In the xenograft model SUM159, the adjusted 10-day TV for o+p was significantly less than TV for p, p-value = 0.0303.
Conclusions
Onvansertib in combination with paclitaxel showed promising results in a subset of breast cancer cells and animal model characterized by the presence of mutp53. Our preclinical results confirm mutp53 as predictive biomarker of synergy and set the feasibility of performing a clinical trial with the combination o+p for mutp53 breast cancer patients.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
K12 Paul Calabresi funding, K12 CA157688.
Disclosure
M. Erlander: Leadership role, Chief Scientific Officer (CSO): Trovagene Oncology. All other authors have declared no conflicts of interest.
Resources from the same session
2786 - Development of a living organoid biobank derived from colorectal cancer patients: towards personalized medicine
Presenter: Federica Papaccio
Session: Poster Display session 2
Resources:
Abstract
3351 - Microsatellite Instability Detection in Colorectal Cancer: 44-Center Comparison between the Idylla MSI Assay and Routine Molecular and Immunohistochemistry Tests on Formalin-Fixed Paraffin-Embedded Tissue
Presenter: Xavier Matias-guiu
Session: Poster Display session 2
Resources:
Abstract
4901 - Expression profile of EPHB3 and its prognostic significance in colorectal cancer progression (Running head: Prognostic value of EPHB3 in colorectal cancers)
Presenter: Bogun Jang
Session: Poster Display session 2
Resources:
Abstract
5030 - A pan-ErbB family inhibitor, AF8c, promotes apoptosis by DR5/Nrf2 activation via ROS in colorectal cancer cells
Presenter: Soyeon Jeong
Session: Poster Display session 2
Resources:
Abstract
5053 - Frequent BRAF, GNAS and SMAD4 mutations identified in Colorectal Mucinous Carcinomas
Presenter: Sun Mi Lee
Session: Poster Display session 2
Resources:
Abstract
5220 - Impact of CCL4 knockout using CRISPR Cas-9 technology on colorectal tumor progression
Presenter: Roba Barakat
Session: Poster Display session 2
Resources:
Abstract
5330 - Independent clinical validation of a gene expression profile to predict benefit of 5-FU in metastatic colorectal cancer
Presenter: Ida Buhl
Session: Poster Display session 2
Resources:
Abstract
5515 - WRN mutated Colorectal Cancer (CRC) is characterized by a distinct molecular and immunological profile
Presenter: Andreas Seeber
Session: Poster Display session 2
Resources:
Abstract
5716 - Mutation analysis of B2M gene in colorectal cancer patients with microsatellite instability
Presenter: Ivana Kašubová
Session: Poster Display session 2
Resources:
Abstract
870 - Selective Wnt/β-catenin small-molecule inhibitor CWP232228 impairs tumor growth of colon cancer
Presenter: Jin Young Kim
Session: Poster Display session 2
Resources:
Abstract