Molecular analysis of XPO1 inhibitor and gemcitabine-nab-paclitaxel combination in KPC pancreatic cancer mouse model.

Abstract

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-KrasG12D/+ ; LSL-Trp53R172H/+ ; 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) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin-bound (nab)-paclitaxel (GemPac). Exporter protein exportin 1 (XPO1) inhibitor selinexor (Sel) with GemPac synergistically inhibited the growth of LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) mouse derived cell line and enhanced the survival of mice. Digital spatial profiling shows that Sel-GemPac causes broad perturbation of PDAC-supporting signalling in the KPC model.

• Authors: Md Hafiz Uddin, Mohammad Najeeb Al-Hallak, Husain Yar Khan, Amro Aboukameel, Yiwei Li, Sahar F Bannoura, Gregory Dyson, Seongho Kim, Yosef Mzannar, Ibrahim Azar, Tanya Odisho, Amr Mohamed, Yosef Landesman, Steve Kim, Rafic Beydoun, Ramzi M Mohammad, Philip A Philip, Anthony F Shields, Asfar S Azmi
• Journal: Clinical and translational medicine (Clin Transl Med) Vol. 13 Issue 12 Pg. e1513 (12 2023) ISSN: 2001-1326 [Electronic] United States
• PMID: 38131168 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

Chemical References

• Xpo1 protein, mouse
• Exportin 1 Protein
• Gemcitabine
• Paclitaxel
• selinexor
• Hydrazines
• Triazoles
• Drug Combinations

Topics

• Animals
• Mice
• Disease Models, Animal
• Pancreatic Neoplasms (drug therapy)
• Carcinoma, Pancreatic Ductal (drug therapy)
• Exportin 1 Protein (antagonists & inhibitors)
• Gemcitabine (administration & dosage)
• Paclitaxel (administration & dosage)
• Hydrazines (administration & dosage)
• Triazoles (administration & dosage)
• Tumor Microenvironment
• Single-Cell Gene Expression Analysis
• Drug Combinations
• Humans