Abstract 3129
Background
The tumor suppressor TP53 is the most frequently mutated gene in solid tumors. Although TP53 decides cell fate and governs initiation of apoptosis, inhibitors targeting mutant TP53 did not yet reached clinical use. Our goal was to identify new potential therapeutic targets in TP53 mutant solid tumors by in silico analysis of multiple large, independent next-generation sequencing and gene chip datasets.
Methods
First, gene expression and mutation data from multiple solid tumors were collected from TCGA and METABRIC databases. Samples were separated based on TP53 mutation status, mutational type and tumor type to identify targetable genes. Differential gene expression was compared using Mann-Whitney test between the mutated (disruptive mutations only) and wild type patient cohorts across all genes. Then, the prognostic value of identified genes was validated in a gene chip-based dataset obtained from the GEO repository. Survival analysis was performed using Cox proportional hazards regression. Significance threshold was set at p < 0.01. Finally, False Discovery Rate was computed to correct for multiple hypothesis testing.
Results
The TCGA dataset include 9,720 patients (21 different cancer types), the Metabric dataset (breast cancer) 1,399 patients, and the GEO dataset (breast, lung, and brain tumors) 7,386 patients. Only genes with higher expression in the TP53 mutant cohort were selected and the list of the top targets was further filtered to include only druggable kinases. The best performing kinases include MPS1 (p = 2.9E-58, FC = 2.82), PLK1 (p = 2.6E-55, FC = 2.55), MELK (p = 5.2E-54, FC = 2.81), and AURKB (p = 2E-53, FC = 3.23). Each of these kinases had a significant prognostic power as well. Of the top 2 (MPS1 and PLK1), both have multiple inhibitors available (for other indications) with PLK1 closest to the clinical use.
Conclusions
Our results suggest that MPS1 (monopolar spindle 1 kinase) and PLK1 (polo like kinase 1) kinases are the strongest druggable targets in TP53 mutant solid tumors.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Semmelweis University.
Funding
National Research, Development and Innovation Office, Hungary.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
3140 - Phase 2 study of olaparib in previously treated advanced solid tumors with homologous recombination repair mutation (HRRm) or homologous recombination repair deficiency (HRD): LYNK-002
Presenter: David Hyman
Session: Poster Display session 3
Resources:
Abstract
2655 - The K-BASKET trial: A prospective phase II biomarker-driven multiple basket trial in Korean solid cancer patients.
Presenter: Seul Kim
Session: Poster Display session 3
Resources:
Abstract
5938 - Cambridge Liquid biopsy “CALIBRATION” study: Can changes in circulating tumour DNA (ctDNA) predict durable tumour responses in patients with advanced oesophageal cancer receiving MEDI4736?
Presenter: Constanza Linossi
Session: Poster Display session 3
Resources:
Abstract
3799 - Validation of a tumour mutational burden workflow on routine histological samples of colorectal cancer and assessment of a cohort with synchronous hepatic metastases
Presenter: Andrea Mafficini
Session: Poster Display session 3
Resources:
Abstract
4647 - Microsatellite Instability Testing and Lynch Syndrome Screening For Colorectal Cancer Patients Through Tumor Sequencing
Presenter: Li Liu
Session: Poster Display session 3
Resources:
Abstract
3231 - "Liquid Withdarw" technique in CT-guided cutting needle lung biopsy: decreased incidence of complications and increased tissue amount for lung cancer molecular testing.
Presenter: Xue Wang
Session: Poster Display session 3
Resources:
Abstract
3282 - WGS Implementation in standard cancer Diagnostics for Every cancer patient (WIDE)
Presenter: Paul Roepman
Session: Poster Display session 3
Resources:
Abstract
5905 - Known and unknown gene fusion detection capabilities of solid tumor laboratories conducting next generation sequencing in 6 countries
Presenter: Steph Finucane
Session: Poster Display session 3
Resources:
Abstract
4238 - Clinical and Analytical Accuracy of a 523 Gene Panel Next-Generation Sequencing (NGS) Assay on Formalin-Fixed Paraffin-Embedded (FFPE) Solid Tumor Samples
Presenter: Ina Deras
Session: Poster Display session 3
Resources:
Abstract
2493 - Methylation analysis of MLH1 using droplet digital PCR and methylation sensitive restriction enzyme.
Presenter: Celine De Rop
Session: Poster Display session 3
Resources:
Abstract