Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer.
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Colonic Neoplasms
/ drug therapy
Colorectal Neoplasms
/ drug therapy
Humans
Myeloid Cell Leukemia Sequence 1 Protein
/ drug effects
Proto-Oncogene Proteins c-bcl-2
/ drug effects
bcl-X Protein
/ drug effects
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
17 10 2020
17 10 2020
Historique:
received:
10
06
2020
accepted:
02
10
2020
revised:
01
10
2020
entrez:
18
10
2020
pubmed:
19
10
2020
medline:
14
5
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33070156
doi: 10.1038/s41419-020-03092-7
pii: 10.1038/s41419-020-03092-7
pmc: PMC7568722
doi:
Substances chimiques
Antineoplastic Agents
0
BCL2L1 protein, human
0
Myeloid Cell Leukemia Sequence 1 Protein
0
Proto-Oncogene Proteins c-bcl-2
0
bcl-X Protein
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
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