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XPO1 inhibition synergizes with PARP1 inhibition in small cell lung cancer by targeting nuclear transport of FOXO3a.
- Source :
-
Cancer letters [Cancer Lett] 2021 Apr 10; Vol. 503, pp. 197-212. Date of Electronic Publication: 2021 Jan 23. - Publication Year :
- 2021
-
Abstract
- Patient mortality rates have remained stubbornly high for the past decades in small cell lung cancer (SCLC) because of having no standard targeted therapies with confirmed advantages at present. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models but have had unsatisfactory clinical results in SCLC. By RNA-seq and isobaric tags for relative and absolute quantification (ITRAQ), we revealed that PARP1 inhibition led to the relocalization of forkhead box-O3a (FOXO3a) from nuclear to cytoplasm. By performing co-Immunoprecipitation (co-IP) and CRISPR-Cas9-mediated knockout plasmid we showed that FOXO3a was subject to exportin 1 (XPO1)-dependent nuclear export. We demonstrated the effects of the PARP inhibitor BMN673 on apoptosis and DNA damage were markedly enhanced by simultaneous inhibition of XPO1 in vitro. The combination of BMN673 and the XPO1 inhibitor selinexor inhibited primary SCLC cell proliferation in mini-patient-derived xenotransplants (miniPDXs) and markedly inhibited tumor growth without significant toxicity in xenograft models. The efficacy was enhanced for more than 2.5 times, compared to the single agent. Based on these findings, we further designed a novel dual PARP-XPO1 inhibitor and showed its effectiveness in SCLC. In this work, we illustrated that combining a PARP inhibitor with an XPO1 inhibitor is associated with significantly improved efficacy and tolerability. Dual PARP-XPO1 inhibition restored the FOXO3a balance and activity in SCLC. Collectively, targeting PARP1 and XPO1 opens new avenues for therapeutic intervention against SCLC, warranting further investigation in potential clinical trials.<br /> (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Subjects :
- Active Transport, Cell Nucleus drug effects
Animals
Cell Line, Tumor
Cell Nucleus metabolism
Cell Proliferation drug effects
Cell Survival drug effects
Cytoplasm metabolism
Drug Synergism
Female
Gene Expression Regulation, Neoplastic drug effects
Humans
Hydrazines pharmacology
Lung Neoplasms metabolism
Mice
Phthalazines pharmacology
Small Cell Lung Carcinoma metabolism
Triazoles pharmacology
Xenograft Model Antitumor Assays
Exportin 1 Protein
Forkhead Box Protein O3 metabolism
Hydrazines administration & dosage
Karyopherins antagonists & inhibitors
Lung Neoplasms drug therapy
Phthalazines administration & dosage
Receptors, Cytoplasmic and Nuclear antagonists & inhibitors
Small Cell Lung Carcinoma drug therapy
Triazoles administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 503
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 33493586
- Full Text :
- https://doi.org/10.1016/j.canlet.2021.01.008