Abstract 1087: CXCR2 and its ligands modulate chemotherapy resistance in pancreatic ductal adenocarcinoma

Abstract Oxysterol-binding protein 2 (OSBP2) is crucial for the promotion of growth and development of cancers, however, its effects in pancreatic ductal adenocarcinoma (PDAC) were still unclear. Here we report the evidence that OSBP2 works as an efficient tumor-associated protein to lead to PDAC extremely malignant characters. We discovered that raised OSBP2 expression in primary tumors was associated with shorter survival in PDAC patients. Therefore, we used immunohistochemistry to analysis the levels of OSBP2 expression in PDAC tissues and adjacent para-cancer tissues. We used wound-healing assay and transwell assay to evaluate the effects of OSBP2 on PDAC cells’ (ASPC-1 and BXPC-3) migration and invasion, respectively. Using CCK-8 and Annexin V / PI double staining, we evaluated the effects of OSBP2 on PDAC cells’ proliferation and apoptosis, respectively. We also explored the effect of OSBP2 on chemosensitivity (gemcitabine and 5-Fluorouracil). And we further validated these findings in vivo of mice. At last, we used western blot to analysis the effect of OSBP2 on PDAC cells’ phenotype. We proved that OSBP2 overexpression promoted PDAC cells’ migration, invasion, proliferation and chemotherapy resistance, decreased apoptosis. OSBP2 overexpression downregulated E-cadherin, and upregulated the levels of N-cadherin, vimentin, Snail, Slug, ZEB1 and β-Catenin. Taken collectively, our findings indicated that OSBP2 exhibited overexpression in PDAC, and upregulation of OSBP2 may promote the progression of PDAC. OSBP2 may have potential diagnostic and therapeutic values in PDAC.

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Phospho-Ser784-VCP Drives Resistance of Pancreatic Ductal Adenocarcinoma to Genotoxic Chemotherapies and Predicts the Chemo-Sensitizing Effect of VCP Inhibitor

Cancers ◽

10.3390/cancers13205076 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5076

Author(s):

Faliang Wang ◽

Kiran Vij ◽

Lin Li ◽

Paarth Dodhiawala ◽

Kian-Huat Lim ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cell Survival ◽

Pancreatic Ductal Adenocarcinoma ◽

Cell Lines ◽

Chemotherapy Resistance ◽

Ductal Adenocarcinoma ◽

Chemotherapy Response ◽

Pdac Cell ◽

Aaa Atpase

Pancreatic ductal adenocarcinoma (PDAC) patients have a dismal prognosis due in large part to chemotherapy resistance. However, a small subset containing defects in the DNA damage response (DDR) pathways are chemotherapy-sensitive. Identifying intrinsic and therapeutically inducible DDR defects can improve precision and efficacy of chemotherapies for PDAC. DNA repair requires dynamic reorganization of chromatin-associated proteins, which is orchestrated by the AAA+ ATPase VCP. We recently discovered that the DDR function of VCP is selectively activated by Ser784 phosphorylation. In this paper, we show that pSer784-VCP but not total VCP levels in primary PDAC tumors negatively correlate with patient survival. In PDAC cell lines, different pSer784-VCP levels are induced by genotoxic chemotherapy agents and positively correlate with genome stability and cell survival. Causal effects of pSer784-VCP on DNA repair and cell survival were confirmed using VCP knockdown and functional rescue. Importantly, DNA damage-induced pSer784-VCP rather than total VCP levels in PDAC cell lines predict their chemotherapy response and chemo-sensitizing ability of selective VCP inhibitor NMS-873. Therefore, pSer784-VCP drives genotoxic chemotherapy resistance of PDAC, and can potentially be used as a predictive biomarker as well as a sensitizing target to enhance the chemotherapy response of PDAC.

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Therapeutic targeting of STAT3 pathways in pancreatic adenocarcinoma: A systematic review of clinical and preclinical literature

PLoS ONE ◽

10.1371/journal.pone.0252397 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0252397

Author(s):

Sarah Peisl ◽

Claudia Mellenthin ◽

Lucie Vignot ◽

Carmen Gonelle-Gispert ◽

Leo Bühler ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Clinical Setting ◽

Chemotherapy Resistance ◽

Ductal Adenocarcinoma ◽

Preclinical Studies ◽

Therapeutic Approaches ◽

Stat3 Pathway ◽

Significant Efficacy ◽

Novel Biomarkers ◽

Preclinical And Clinical Studies

Background/Objectives Pancreatic ductal adenocarcinoma is a highly lethal disease with increasing incidence. Due to high resistance, chemo/radiotherapy has limited success in pancreatic cancer and only marginally prolongs patient survival. Therefore, novel biomarkers and therapeutic targets are needed. In the present review, we performed a comprehensive summary of therapeutic approaches targeting the GP130/JAK/STAT3 pathway. Methods We systematically reviewed the PubMed and Embase databases for preclinical and clinical studies, from inception to October 4, 2020, on drugs targeting the GP130/JAK/STAT3 pathway. Bias assessments and qualitative analyses were performed. Results Twenty-five preclinical and nine clinical trials were included in the review. All preclinical studies reported a favorable outcome in terms of pancreatic ductal adenocarcinoma progression. Futhermore, drugs targeting the GP130/JAK/STAT3 pathway were shown to be efficient chemosensitizers. However, high publication bias was assumed. In the clinical setting, bazedoxifene and itacitinib improved patient outcomes. Conclusion Preclinical studies strongly suggest significant efficacy of drugs targeting GP130/JAK/STAT3 in the treatment of pancreatic ductal adenocarcinoma and that these molecules are effective chemosensitizers. Though only a few trials have shown the efficacy in a clinical setting, the STAT3 pathway remains a promising drug target for future treatment of pancreatic ductal adenocarcinoma and may help overcome chemotherapy resistance.

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