Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer

Anna-Lena Scherr,Philipp J Jost,Dirk Jäger,Jörg Trojan,Stefan Fröhling,Christoph E Heilig,Georg Gdynia,Mathias Heikenwälder ,Johanna Falkenhorst,Svetlana Grekova ,Henning Schulze‐Bergkamen ,Jens T Siveke ,Anna Lena Illert ,Loredana Vecchione,Klaus Schulze–Osthoff ,Tobias Gehrig,Albrecht Stenzinger,Peter Schirmacher,Melanie Boerries,Oliver Waidmann,Ivan Jelas,Hanno Glimm,Andreas Möck ,Benjamin Goeppert,Praveen Rhadakrishnan,Martin Schneider,Michael Bitzer,Nathalie Schmitt,Nisar P Malek,Paula Hoffmeister,Felix Korell,Klaus H Metzeler,Benedikt Brors,Bruno Köhler

doi:10.1038/s41419-020-03092-7

Abstract

Since metastatic colorectal cancer (CRC) is a leading cause of cancer-related death, therapeutic approaches overcoming primary and acquired therapy resistance are an urgent medical need. In this study, the efficacy and toxicity of high-affinity inhibitors targeting antiapoptotic BCL-2 proteins (BCL-2, BCL-XL, and MCL-1) were evaluated. By RNA sequencing analysis of a pan-cancer cohort comprising >1500 patients and subsequent prediction of protein activity, BCL-XL was identified as the only antiapoptotic BCL-2 protein that is overactivated in CRC. Consistently, pharmacologic and genetic inhibition of BCL-XL induced apoptosis in human CRC cell lines. In a combined treatment approach, targeting BCL-XL augmented the efficacy of chemotherapy in vitro, in a murine CRC model, and in human ex vivo derived CRC tissue cultures. Collectively, these data show that targeting of BCL-XL is efficient and safe in preclinical CRC models, observations that pave the way for clinical translation.

Highlights

Colorectal cancer (CRC) ranks among the most frequent cancers worldwide and represents a leading cause of cancer-related death[1,2]
Since mRNA levels not necessarily correlate with protein activity, we used the metaVIPER algorithm to infer the activity of antiapoptotic BCL-2 proteins from RNA sequencing data
Since avoidance of apoptosis is a general hallmark of tumors, cell death preventing factors, such as antiapoptotic members of the BCL-2 protein family and their potential inhibition, are in the focus of cancer research[41]

Summary

Introduction

Colorectal cancer (CRC) ranks among the most frequent cancers worldwide and represents a leading cause of cancer-related death[1,2]. In the metastasized situation (UICC stage IV), chemotherapy remains the backbone of standard of care therapeutic approaches[3]. In addition to poly-chemotherapy, targeting EGFR and VEGFR complements therapeutic regimes in clinical practice[4]. In the Primary treatment failure as well as acquired resistance is determined by defective cell death signaling[9,10,11]. In several studies it has been shown that cells accumulate proapoptotic proteins in the course of oncogenic transformation, caused by check point evasion and DNA damage response[12,13]. A considerable percentage of tumor cells manages to escape from cell death

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