ABL allosteric inhibitors synergize with statins to enhance apoptosis of metastatic lung cancer cells.
Allosteric Regulation
/ drug effects
Animals
Apoptosis
/ drug effects
Cell Line, Tumor
Drug Synergism
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
/ pharmacology
Lung Neoplasms
/ drug therapy
Mice
Mice, Nude
Neoplasm Metastasis
Oncogene Proteins v-abl
/ antagonists & inhibitors
Protein Kinase Inhibitors
/ pharmacology
Signal Transduction
/ drug effects
Xenograft Model Antitumor Assays
ABL kinases
HMGCR
brain metastasis
lung adenocarcinoma
statins
therapy resistance
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
26 10 2021
26 10 2021
Historique:
received:
17
12
2020
revised:
29
08
2021
accepted:
04
10
2021
entrez:
27
10
2021
pubmed:
28
10
2021
medline:
11
2
2022
Statut:
ppublish
Résumé
Targeting mitochondrial metabolism has emerged as a treatment option for cancer patients. The ABL tyrosine kinases promote metastasis, and enhanced ABL signaling is associated with a poor prognosis in lung adenocarcinoma patients. Here we show that ABL kinase allosteric inhibitors impair mitochondrial integrity and decrease oxidative phosphorylation. To identify metabolic vulnerabilities that enhance this phenotype, we utilized a CRISPR/Cas9 loss-of-function screen and identified HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway and target of statin therapies, as a top-scoring sensitizer to ABL inhibition. Combination treatment with ABL allosteric inhibitors and statins decreases metastatic lung cancer cell survival in vitro in a synergistic manner. Notably, combination therapy in mouse models of lung cancer brain metastasis and therapy resistance impairs metastatic colonization with a concomitant increase in animal survival. Thus, metabolic combination therapy might be effective to decrease metastatic outgrowth, leading to increased survival for lung cancer patients with advanced disease.
Identifiants
pubmed: 34706244
pii: S2211-1247(21)01350-4
doi: 10.1016/j.celrep.2021.109880
pmc: PMC8579324
mid: NIHMS1751626
pii:
doi:
Substances chimiques
Hydroxymethylglutaryl-CoA Reductase Inhibitors
0
Oncogene Proteins v-abl
0
Protein Kinase Inhibitors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
109880Subventions
Organisme : NCI NIH HHS
ID : P50 CA190991
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA206348
Pays : United States
Organisme : NCI NIH HHS
ID : F99 CA245732
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA246133
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK106090
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA207083
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014236
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA195549
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007171
Pays : United States
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests A.M.P. is a consultant and advisory board member for The Pew Charitable Trusts. A.M.P. holds patent number U.S. 9,931,342 B2 related to this work. All other authors declare no competing interests.
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