Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, and the mortality of patients with PDAC has not significantly decreased over the last few decades. Novel strategies exhibiting promising effects in preclinical or phase I/II clinical trials are often situated in an embarrassing condition owing to the disappointing results in phase III trials. The efficacy of the current therapeutic regimens is consistently compromised by the mechanisms of drug resistance at different levels, distinctly more intractable than several other solid tumours. In this review, the main mechanisms of drug resistance clinicians and investigators are dealing with during the exploitation and exploration of the anti-tumour effects of drugs in PDAC treatment are summarized. Corresponding measures to overcome these limitations are also discussed.

Increased insulin level (or “hyperinsulinemia”) is a common phenomenon in pancreatic ductal adenocarcinoma (PDA) patients and signals poor clinical outcomes. Insulin is safe in low PDA risk population, while insulin significantly promotes PDA risk in high PDA risk population. The correlation between insulin and PDA is a reciprocal self-reinforcing relationship. On the one hand, pancreatic cancer cells synthesize multiple molecules to cause elevated peripheral insulin resistance, thus enhancing hyperinsulinemia. On the other hand, insulin promotes pancreatic cancer initiation and sustains PDA development by eliciting tumorigenic inflammation, regulating lipid and glucose metabolic reprogram, overcoming apoptosis through the crosstalk with IGF-1, stimulating cancer metastasis, and activating tumor microenvironment formation (inflammation, fibrosis, and angiogenesis). Currently, taking glucose sensitizing agents, including metformin, SGLT-2 inhibitor, and GLP-1 agonist, is an effective way of lowering insulin levels and controlling PDA development at the same time. In the future, new drugs targeting insulin-related signal pathways may pave a novel way for suppressing PDA initiation and progression.

Background Sodium glucose transporters (SGLTs) play vital roles in glucose uptake in many solid cancers, including pancreatic cancer (PC). However, their expression profile in pancreatic cancer and correlation with prognosis are not clear. Thus, we aimed to analyse the expression profile and prognostic significance of SGLT-1 and SGLT-2 in PC. Methods Eighty-eight patients with pancreatic ductal adenocarcinoma (PDAC) undergoing surgery in Huashan Hospital, Fudan University, from July 2017 to June 2020 were enrolled in the study. Specimens for immunohistochemistry were obtained through surgical resection. Bioinformatics analysis was performed based on the Gene Expression Omnibus (GEO), Oncomine and The Cancer Genome Atlas (TCGA) databases. The statistics were calculated using IBM SPSS Statistics, version 20 and R 4.1.1. P values lower than 0.05 were considered to indicate statistical significance. Results SGLT-1 but not SGLT-2 was significantly overexpressed in PDAC. Survival analysis showed that the median overall survival (OS) and progression-free survival (PFS) of patients with high SGLT-1 expression were significantly longer than that of patients with low SGLT-1 expression. Cox regression indicated that high SGLT-1 expression was an independent predictor for a better prognosis, while residual tumour status (R1 and R2) was an independent risk factor for a poor prognosis. Finally, PDZK1-interacting protein 1 (PDZK1IP1), a protein participating in the generation of reactive oxygen species, was overexpressed in PDAC and its expression was significantly correlated with SGLT-1. Conclusions SGLT-1 but not SGLT-2 was overexpressed in PDAC, and the overexpression of SGLT-1 could be a predictor of a better prognosis. Residual tumour status (R1 and R2) was a risk factor for poor prognosis and disease progression.

PurposeGemcitabine (GEM) is the first-line chemotherapeutic drug for pancreatic cancer treatment in clinical practice. However, many reasons can reduce the efficacy of GEM, among which the high expression of ATP-binding cassette (ABC) transporters is a significant factor. In this study, we aimed to investigate the antitumor effect of gemcitabine-loaded human serum albumin nanoparticle (GEM-HSA-NP) on GEM-resistant pancreatic cancer cells induced by the high expression of ABC transporters, namely multidrug resistance protein 1/P-gp/ABCB1 (MDR1) and multidrug resistance-associated protein 1/ ABCC1 (MRP1).MethodsMDR1 and MRP1 were stably overexpressed via lentiviral transduction in the pancreatic cancer cell lines BxPC3 and PANC1. Proliferation inhibition assays, cell cycle arrest and apoptosis analyses were conducted to examine the antitumor effect of GEM-HSA-NP. In addition, intracellular ATP levels were determined to explore the potential mechanisms implicated preliminarily.ResultsWhen administered to GEM-resistant cancer cells, GEM-HSA-NP displayed its antitumor effect by promoting the inhibition of proliferation, cell cycle arrest, and apoptosis induction. Intracellular ATP depletion, caused by the albumin component of GEM-HSA-NP was proposed to be potentially involved in the modulation of ABC transporter activity.ConclusionGEM-HSA-NP can effectively overcome GEM-resistance induced by MDR1 and MRP1 overexpression, which highlights its potential value in a clinical setting.

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Purpose Pancreatic cyst neoplasm (PCN) is a precursor of pancreatic cancer. Previous studies reported PCN was often concurrent with diabetes. We aim to examine the association between diabetes with PCN malignancy and to detect the potential role of diabetes in PCN management and treatment. Patients and Methods A total of 224 patients who were diagnosed with the three major types of PCN (IPMN, MCN, and SCN) and underwent surgical resection were selected. Patients were divided into three groups (normal group, new-onset diabetes group (NODM) (<4years), and long-standing diabetes group (LSDM) (>4years)) according to diabetic history and diagnostic time interval. Diabetes, fast blood glucose level, HbA1c, and insulin resistance level were measured. Malignant PCN (mPCN) radiological features (worrisome features and high-risk stigmata) were analyzed. Pathological features (PCN type, dysplasia grade, tumor stage, and tumor volume) and immunohistology of Ki67 and SMAD4 were performed. Diagnostic efficacy of each variable was determined by the ROC curve. mPCN diagnosis was the main outcome in diagnostic prediction and overall survival as the glucose controlling outcome variables. Results Diabetes groups (NODM and LSDM) showed difference with the normal group in age, weight loss, malignancy, CA19-9 value, CEA value, Ki-67 value, tumor volume, pathological grade, and a lowered pancreatic fistula risk. NODM was related to insulin resistance, weight loss, and SMAD4 mutation. NODM (87.3%) and high insulin resistance rate (93.6%) significantly increased the sensitivity of radiological evidence-based mPCN diagnosis. Moreover, long-standing diabetes and elevated HbA1c led to reduced survival in mPCN patients than the normal PCN group. Anti-diabetic drugs showed limited influence on PCN malignancy and tumor volume. Conclusion NODM in PCN patients was associated with malignancy, insulin resistance, weight loss, and SMAD4 mutation. Prediabetic status and NODM diagnosis enhanced the diagnostic accuracy of radiological standards (worrisome features and high-risk stigmata). Stable glucose surveillance is necessary for mPCN patients’ survival.

Pancreatic ductal adenocarcinoma (PDA) is often concomitant with diabetes mellitus, which mainly manifests as an increased blood glucose level. Previous studies revealed that diabetic status reduced the survival and blunted gemcitabine sensitivity in PDA patients. This study is aimed at analyzing the mechanism of elevated gemcitabine resistance and cancer invasion ability under high glucose environment. We selected 129 patients with 22 surgical resected samples from 2015 to 2021, who underwent pancreatic surgery in Huashan Hospital. The gene expression and clinical data of PDA were obtained from The Cancer Genome Atlas (TCGA) website and were analyzed by R software. Cell viability assays and flow cytometry were applied to detect gemcitabine sensitivity and apoptosis levels in pancreatic cancer cells. Wound healing and Transwell tests were used to analyze the invasion and metastasis of cancer cells. Streptozotocin (STZ) was used to establish a hyperglycemic mouse model for the in vivo study. In this study, diabetic PDA gemcitabine users showed reduced survival compared to euglycemic PDA gemcitabine users. Clinical samples and laboratory studies revealed that MMP-3 expression was associated with glucose concentration and diabetic status. Elevated MMP-3 expression was positively related to cancer invasion and gemcitabine resistance in PDA cells and gemcitabine resistant PDA cells. Blocking MMP-3 expression inhibited gemcitabine resistance and cancer progression in cellular and animal models. MMP-3 was closely related to the expression of RRM1, a gemcitabine metabolism-related gene. Reactive oxygen species (ROS) level increased under higher glucose concentrations and was mediated by NOX4. ROS determined the MMP-3 expression in pancreatic cancer cells. Inhibiting NOX4 expression effectively suppressed MMP-3 expression, gemcitabine resistance, and cancer invasion. In conclusion, a high glucose environment induces gemcitabine resistance and cancer invasion via ROS/MMP-3 signaling pathway. MMP-3 can be a potential novel target for suppressing gemcitabine resistance and invasion in PDA.