Identification of relevant drugable targets in diffuse large B-cell lymphoma using a genome-wide unbiased CD20 guilt-by association approach

PloS One
Mathilde R W de JongTom van Meerten

Abstract

Forty percent of patients with diffuse large B-cell lymphoma (DLBCL) show resistant disease to standard chemotherapy (CHOP) in combination with the anti-CD20 monoclonal antibody rituximab (R). Although many new anti-cancer drugs were developed in the last years, it is unclear which of these drugs can be safely combined to improve standard therapy without antagonizing anti-CD20 efficacy. In this study, we aimed to identify rituximab compatible drug-target combinations for DLBCL. For this, we collected gene expression profiles of 1,804 DLBCL patient samples. Subsequently, we performed a guilt-by-association analysis with MS4A1 (CD20) and prioritized the 500 top-ranked CD20-associated gene probes for drug-target interactions. This analysis showed the well-known genes involved in DLBCL pathobiology, but also revealed several genes that are relatively unknown in DLBCL, such as WEE1 and PARP1. To demonstrate potential clinical relevance of these targets, we confirmed high protein expression of WEE1 and PARP1 in patient samples. Using clinically approved WEE1 and PARP1 inhibiting drugs in combination with rituximab, we demonstrated significantly improved DLBCL cell killing, also in rituximab-insensitive cell lines. In conclusion, as e...Continue Reading

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Citations

Dec 6, 2019·International Journal of Molecular Sciences·Mathilde Rikje Willemijn de JongTom van Meerten
Jan 11, 2020·Frontiers in Oncology·Antonello Di PaoloSara Galimberti
Sep 23, 2020·Journal of Hematology & Oncology·Andrea Ghelli Luserna di RoràGiorgia Simonetti
Nov 11, 2019·Cancers·Mathilde Rikje Willemijn de JongTom van Meerten
Dec 31, 2020·International Journal of Molecular Sciences·Isaias Hernández-VerdinAgusti Alentorn
Sep 7, 2020·Cancer Treatment Reviews·Laura CarrassaFrancesco Bertoni

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Methods Mentioned

BETA
Protein Assay
electrophoresis
flow cytometry
flowcytometry
biopsies

Software Mentioned

Winlist
GCOS XDA
GPL
GSEAs
RMAExpress
Biocarta
Graphpad PRISM
GEO
Enrichr
Affymetrix Power Tools

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