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

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

doi:10.1038/s41419-020-03092-7

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

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

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

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.

Original language	English
Article number	875
Journal	Cell Death and Disease
Volume	11
Issue number	10
DOIs	https://doi.org/10.1038/s41419-020-03092-7
State	Published - 1 Oct 2020
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41419-020-03092-7

Cite this

Scherr, A. L., Mock, A., Gdynia, G., Schmitt, N., Heilig, C. E., Korell, F., Rhadakrishnan, P., Hoffmeister, P., Metzeler, K. H., Schulze-Osthoff, K., Illert, A. L., Boerries, M., Trojan, J., Waidmann, O., Falkenhorst, J., Siveke, J., Jost, P. J., Bitzer, M., Malek, N. P., ... Köhler, B. C. (2020). Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer. Cell Death and Disease, 11(10), Article 875. https://doi.org/10.1038/s41419-020-03092-7

@article{f78e08fcc7234587966045464aeb51bc,

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

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.",

author = "Scherr, {Anna Lena} and Andreas Mock and Georg Gdynia and Nathalie Schmitt and Heilig, {Christoph E.} and Felix Korell and Praveen Rhadakrishnan and Paula Hoffmeister and Metzeler, {Klaus H.} and Klaus Schulze-Osthoff and Illert, {Anna L.} and Melanie Boerries and J{\"o}rg Trojan and Oliver Waidmann and Johanna Falkenhorst and Jens Siveke and Jost, {Philipp J.} and Michael Bitzer and Malek, {Nisar P.} and Loredana Vecchione and Ivan Jelas and Benedikt Brors and Hanno Glimm and Albrecht Stenzinger and Grekova, {Svetlana P.} and Tobias Gehrig and Henning Schulze-Bergkamen and Dirk J{\"a}ger and Peter Schirmacher and Mathias Heikenwalder and Benjamin Goeppert and Martin Schneider and Stefan Fr{\"o}hling and K{\"o}hler, {Bruno C.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = oct,

day = "1",

doi = "10.1038/s41419-020-03092-7",

language = "English",

volume = "11",

journal = "Cell Death and Disease",

issn = "2041-4889",

publisher = "Springer Nature",

number = "10",

}

Scherr, AL, Mock, A, Gdynia, G, Schmitt, N, Heilig, CE, Korell, F, Rhadakrishnan, P, Hoffmeister, P, Metzeler, KH, Schulze-Osthoff, K, Illert, AL, Boerries, M, Trojan, J, Waidmann, O, Falkenhorst, J, Siveke, J, Jost, PJ, Bitzer, M, Malek, NP, Vecchione, L, Jelas, I, Brors, B, Glimm, H, Stenzinger, A, Grekova, SP, Gehrig, T, Schulze-Bergkamen, H, Jäger, D, Schirmacher, P, Heikenwalder, M, Goeppert, B, Schneider, M, Fröhling, S & Köhler, BC 2020, 'Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer', Cell Death and Disease, vol. 11, no. 10, 875. https://doi.org/10.1038/s41419-020-03092-7

TY - JOUR

T1 - Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer

AU - Scherr, Anna Lena

AU - Mock, Andreas

AU - Gdynia, Georg

AU - Schmitt, Nathalie

AU - Heilig, Christoph E.

AU - Korell, Felix

AU - Rhadakrishnan, Praveen

AU - Hoffmeister, Paula

AU - Metzeler, Klaus H.

AU - Schulze-Osthoff, Klaus

AU - Illert, Anna L.

AU - Boerries, Melanie

AU - Trojan, Jörg

AU - Waidmann, Oliver

AU - Falkenhorst, Johanna

AU - Siveke, Jens

AU - Jost, Philipp J.

AU - Bitzer, Michael

AU - Malek, Nisar P.

AU - Vecchione, Loredana

AU - Jelas, Ivan

AU - Brors, Benedikt

AU - Glimm, Hanno

AU - Stenzinger, Albrecht

AU - Grekova, Svetlana P.

AU - Gehrig, Tobias

AU - Schulze-Bergkamen, Henning

AU - Jäger, Dirk

AU - Schirmacher, Peter

AU - Heikenwalder, Mathias

AU - Goeppert, Benjamin

AU - Schneider, Martin

AU - Fröhling, Stefan

AU - Köhler, Bruno C.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85092697623&partnerID=8YFLogxK

U2 - 10.1038/s41419-020-03092-7

DO - 10.1038/s41419-020-03092-7

M3 - Article

C2 - 33070156

AN - SCOPUS:85092697623

SN - 2041-4889

VL - 11

JO - Cell Death and Disease

JF - Cell Death and Disease

IS - 10

M1 - 875

ER -

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

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this