2. Academic Validation
  3. XPO1 inhibition synergizes with PARP1 inhibition in small cell lung cancer by targeting nuclear transport of FOXO3a

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

  • Cancer Lett. 2021 Apr 10;503:197-212. doi: 10.1016/j.canlet.2021.01.008.
Jingya Wang 1,  Tao Sun 2,  Zhaoting Meng 1,  Liuchun Wang 1,  Mengjie Li 1,  Jinliang Chen 1,  Tingting Qin 1,  Jiangyong Yu 3,  Miao Zhang 4,  Zhixin Bie 5,  Zhiqiang Dong 6,  Xiangli Jiang 1,  Li Lin 1,  Cuicui Zhang 1,  Zhujun Liu 1,  Richeng Jiang 1,  Guang Yang 7,  Lin Li 8,  Yan Zhang 9,  Dingzhi Huang 10
Affiliations

Affiliations

  • 1 Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, PR China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China; Tianjin's Clinical Research Center for Cancer, PR China; Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin, 300060, PR China.
  • 2 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, PR China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, PR China.
  • 3 Department of Medical Oncology, Beijing Hospital, National Center of Gerontology, PR China; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China.
  • 4 Department of Oncology, The No.1 Hospital of Shijiazhuang, Shijiazhuang, Hebei, 050010, PR China.
  • 5 Minimally Invasive Tumor Therapies Center, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China.
  • 6 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, PR China.
  • 7 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, PR China. Electronic address: guang.yang@nankai.edu.cn.
  • 8 Department of Medical Oncology, Beijing Hospital, National Center of Gerontology, PR China; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China. Electronic address: lilin2450@bjhmoh.cn.
  • 9 Department of Oncology, The No.1 Hospital of Shijiazhuang, Shijiazhuang, Hebei, 050010, PR China. Electronic address: zhangyan201810@163.com.
  • 10 Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, PR China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China; Tianjin's Clinical Research Center for Cancer, PR China; Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin, 300060, PR China. Electronic address: huangdingzhi@tjmuch.com.
PMID: 33493586 DOI: 10.1016/j.canlet.2021.01.008
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.

Keywords

FOXO3a; Nuclear translocation; PARP inhibitor; Small cell lung cancer; XPO1 inhibitor.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16106
    99.89%, PARP Inhibitor