التفاصيل البيبلوغرافية
| العنوان: |
Molecular analysis of XPO1 inhibitor and gemcitabine–nab‐paclitaxel combination in KPC pancreatic cancer mouse model |
| المؤلفون: |
Uddin, Md. Hafiz, Al‐Hallak, Mohammad Najeeb, Khan, Husain Yar, Aboukameel, Amro, Li, Yiwei, Bannoura, Sahar F., Dyson, Gregory, Kim, Seongho, Mzannar, Yosef, Azar, Ibrahim, Odisho, Tanya, Mohamed, Amr, Landesman, Yosef, Kim, Steve, Beydoun, Rafic, Mohammad, Ramzi M., Philip, Philip A., Shields, Anthony F., Azmi, Asfar S. |
| المصدر: |
Clinical and Translational Medicine ; volume 13, issue 12 ; ISSN 2001-1326 2001-1326 |
| بيانات النشر: |
Wiley |
| سنة النشر: |
2023 |
| المجموعة: |
Wiley Online Library (Open Access Articles via Crossref) |
| الوصف: |
Background The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin‐bound (nab)‐paclitaxel (GemPac) necessitating the need for a more effective treatment strategy for this refractory disease. Previously, we have demonstrated that nuclear exporter protein exportin 1 (XPO1) is a valid therapeutic target in PDAC, and the selective inhibitor of nuclear export selinexor (Sel) synergistically enhances the efficacy of GemPac in pancreatic cancer cells, spheroids and patient‐derived tumours, and had promising activity in a phase I study. Methods Here, we investigated the impact of selinexor–gemcitabine–nab‐paclitaxel (Sel‐GemPac) combination on LSL‐Kras G12D/+ ; LSL‐Trp53 R172H/+ ; Pdx1‐Cre (KPC) mouse model utilising digital spatial profiling (DSP) and single nuclear RNA sequencing (snRNAseq). Results Sel‐GemPac synergistically inhibited the growth of the KPC tumour‐derived cell line. The Sel‐GemPac combination reduced the 2D colony formation and 3D spheroid formation. In the KPC mouse model, at a sub‐maximum tolerated dose (sub‐MTD) , Sel‐GemPac enhanced the survival of treated mice compared to controls ( p < .05). Immunohistochemical analysis of residual KPC tumours showed re‐organisation of tumour stromal architecture, suppression of proliferation and nuclear retention of tumour suppressors, such as Forkhead Box O3a (FOXO3a). DSP revealed the downregulation of tumour promoting genes such as chitinase‐like protein 3 (CHIL3/CHI3L3/YM1) and multiple pathways including phosphatidylinositol 3'‐kinase‐Akt (PI3K‐AKT) signalling. The snRNAseq demonstrated a significant loss of cellular clusters in the Sel‐GemPac‐treated mice tumours including the CD44+ stem cell population. Conclusion Taken together, these results demonstrate that the Sel‐GemPac treatment caused broad perturbation of PDAC‐supporting signalling networks in the KPC mouse model. Highlights The majority of pancreatic ductal adenocarcinoma (PDAC) ... |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1002/ctm2.1513 |
| الإتاحة: |
https://doi.org/10.1002/ctm2.1513Test |
| حقوق: |
http://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: |
edsbas.E02B4B73 |
| قاعدة البيانات: |
BASE |
