XPO1 inhibition synergizes with PARP1 inhibition in small cell lung cancer by targeting nuclear transport of FOXO3a

• Published in: Cancer letters Vol. 503; pp. 197 - 212
• Main Authors: Wang, Jingya, Sun, Tao, Meng, Zhaoting, Wang, Liuchun, Li, Mengjie, Chen, Jinliang, Qin, Tingting, Yu, Jiangyong, Zhang, Miao, Bie, Zhixin, Dong, Zhiqiang, Jiang, Xiangli, Lin, Li, Zhang, Cuicui, Liu, Zhujun, Jiang, Richeng, Yang, Guang, Li, Lin, Zhang, Yan, Huang, Dingzhi
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 10.04.2021; Elsevier Limited
• Subjects: Active Transport, Cell Nucleus - drug effects; Animals; Antibodies; Antigens; Apoptosis; Cancer therapies; Cell Line, Tumor; Cell Nucleus - metabolism; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Clinical trials; CRISPR; Cytoplasm; Cytoplasm - metabolism; Deoxyribonucleic acid; DNA; DNA damage; Drug Synergism; Exportin 1 Protein; Female; Forkhead Box Protein O3 - metabolism; Forkhead protein; FOXO3 protein; FOXO3a; Gene Expression Regulation, Neoplastic - drug effects; Humans; Hydrazines - administration & dosage; Hydrazines - pharmacology; Immunoprecipitation; Karyopherins - antagonists & inhibitors; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Mass spectrometry; Medical prognosis; Mice; Nuclear translocation; Nuclear transport; PARP inhibitor; Phosphorylation; Phthalazines - administration & dosage; Phthalazines - pharmacology; Poly(ADP-ribose) polymerase; Proteins; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Ribose; Scientific imaging; Small cell lung cancer; Small cell lung carcinoma; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - metabolism; Toxicity; Transcription factors; Triazoles - administration & dosage; Triazoles - pharmacology; Xenograft Model Antitumor Assays; Xenografts; XPO1 inhibitor; IHC; CCLE; IKKs; HR; PARP; ChIP; mini-PDX; DDR; XPO1; qPCR; ITRAQ; PFS; SCLC; KOG; SSB; OS; CI; PARP inhibitor; GO; Akt; Co-IP; Small cell lung cancer; MMR; Nuclear translocation; XPO1 inhibitor; FOXO3a; HE
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2021.01.008

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. •PARP1 inhibition led to the relocalization of FOXO3a from nuclear to cytoplasm in small cell lung cancer.•FOXO3a was subject to XPO1–dependent nuclear export.•The effects of the PARP inhibitor are markedly enhanced by simultaneous inhibition of XPO1 in small cell lung cancer.•The combination of PARP and XPO1 inhibition emerges as a promising method for clinical small cell lung cancer treatment.