The small GTPase Ran has emerged as a key player in cancer metastasis. Our previous studies demonstrated that Ran drives pancreatic cancer metastasis by modulating androgen receptor (AR) expression. However, the detailed mechanisms by which Ran regulates AR expression remain unclear. This study aimed to elucidate the regulatory mechanisms through which Ran influences AR expression in the context of pancreatic cancer metastasis. We observed elevated levels of Ran, osteopontin (OPN), and AR in metastatic lymph node tissues, with OPN positively correlated with either Ran or AR expression. Ran silencing led to decreased levels of OPN and AR, whereas Ran upregulation increased their expression. Notably, OPN overexpression restored AR levels in Ran-silenced cells, whereas OPN knockdown diminished the inductive effect of Ran on AR expression. Additionally, OPN knockdown decreased AR expression and was associated with reduced activation of the PI3K/AKT signaling pathway. Functional assays revealed that silencing OPN significantly impaired the mobility and invasion of pancreatic cancer cells and restricted hepatic metastasis. Conversely, OPN overexpression restored the impaired metastasis caused by Ran knockdown. Furthermore, inhibiting PI3K/AKT signaling abolished the promoting effects of either Ran or OPN on pancreatic cancer metastasis. Importantly, re-expressing AR reversed the inhibitory effects of Ran or OPN silencing on the mobility and invasion of pancreatic cancer cells. In summary, Ran induces AR expression through the regulation of the OPN-PI3K/AKT signaling cascade. The Ran-OPN-PI3K/AKT-AR signaling pathway is crucial for driving pancreatic cancer metastasis.

The application of magnetite nanoparticles (MagNPs) for photothermal therapy (MagNP-PTT) has recently expanded to cancer treatment. This study introduces MagNP-PTT in a tumor-on-a-chip model to target highly aggressive pancreatic ductal adenocarcinoma (PDAC). A tumor-on-chip system was developed using PANC-1 PDAC cells embedded in a collagen type I extracellular matrix and cultured for 1 week to form tumor spheroids. This platform offers a framework for applying PTT in a model system that aims to mimic the native tumor microenvironment. MagNPs efficiently penetrate the tumor spheroids, achieving controlled heating via near-infrared (NIR) light. By adjusting nanoparticle concentration and laser power, temperature increments of 2 °C between 38-48 °C were established. Temperatures above 44 °C significantly increased cell death, while lower temperatures allowed partial recovery. Beyond inducing cancer cell death, MagNP-PTT altered the extracellular matrix and triggered a slight epithelial-mesenchymal transition marked by increased vimentin expression. These findings highlight MagNP-PTT as a dual-action therapy, targeting both tumor cells and their microenvironment, offering an alternative approach for overcoming stromal barriers in pancreatic cancer treatment.

Pancreatic cancer is characterized by high rates of metastasis, recurrence, and chemoresistance, contributing to its poor prognosis. Transforming growth factor-β2 (TGF-β2), a member of the TGF-β family, plays a pivotal role in promoting cancer cell metastasis and mediating chemoresistance, particularly in advanced stages of tumor progression. However, the precise role of TGF-β in chemoresistance and metastasis in pancreatic cancer has not been studied yet. In the current study, we investigated the potential of human TGF-β2 antisense oligonucleotides (TGF-β2i) to enhance the chemosensitivity to gemcitabine in pancreatic cancer, using human pancreatic cancer cell lines (hPCCs; PANC-1, MIA PaCa-2, and AsPC-1), a co-culture model with human pancreatic stellate cells (hPSCs), a cancer-associated fibroblast-integrated pancreatic cancer organoid model (CIPCO), and an orthotopic xenograft mouse model. TGF-β2i decreased cell proliferation, migration, and viability in hPCCs, and its combination with gemcitabine exhibited a synergistic effect in PANC-1 and MIA PaCa-2 cells. Flow cytometry demonstrated a decrease in CD44 +CD24 +EpCAMHigh cancer stem-like cell populations following TGF-β2i treatment. In co-culture models, hPSCs-induced enhancement of hPCCs migration was attenuated by TGF-β2i. In the CIPCOs, TGF-β2i suppressed the gemcitabine-induced expression of extracellular matrix components such as COL1A1 and VIM. Furthermore, in an orthotopic mouse model generated by co-inoculating hPCCs and hPSCs into the pancreatic wall, co-treatment of TGF-β2i with gemcitabine significantly delayed tumor growth and metastasis to the liver compared to vehicle control. These findings suggest that TGF-β2i enhances chemosensitivity and suppresses metastatic properties by regulating both tumor-intrinsic and -extrinsic factors, indicating that targeting TGF-β2 could be a promising strategy for managing pancreatic cancer.

Chemotherapy resistance contributes to the unsatisfied prognosis in pancreatic cancer (PC) patients. Heat shock protein beta-1 (HSPB1) plays a tumor promoting role in PC by inhibiting ferroptosis. This study aims to explore whether high expression of HSPB1 was responsible for ferroptosis and gemcitabine (GEM) resistance in PC. Here, we found that HSPB1 was upregulated in GEM-resistant PC cells and tumor tissues, as confirmed by RT-qPCR and Western blotting assays. Knockdown of HSPB1 enhanced GEM sensitivity, decreased the abilities of proliferation and invasion, and promoted apoptosis in GEM-resistant PC cells. Utilizing commercial kits, HSPB1 inhibition triggered ferroptosis, as indicated by increased levels of reactive oxygen species, malondialdehyde, and Fe2+, along with reduced glutathione (GSH) levels. Furthermore, the methylation specific PCR (MSP) results demonstrated a significant decrease in the methylation level of annexin A2 (ANXA2) CpG. The Chromatin immunoprecipitation (ChIP), ChIP-Re-ChIP, and Co-IP experiments revealed that HSPB1 interacts with lysine-specific histone demethylase 1A (KDM1A), recruiting KDM1A-CoREST complex to the ANXA2 promoter to enhance ANXA2 expression through demethylation of H3K9me2. Additionally, ANXA2 depletion further inhibited cell proliferation and invasion and induced ferroptosis in KDM1A-silenced cells, whereas ANXA2 overexpression produced the opposite effects. Finally, HSPB1 overexpression reduced gemcitabine sensitivity by promoting tumor growth in nude mice. Altogether, HSPB1 promoted ANXA2 expression by facilitating H3K9me2 demethylation through the recruitment of KDM1A-CoREST complex to the ANXA2 promoter, thereby inhibiting ferroptosis and enhancing GEM resistance in PC. These data provided a new insight for overcoming GEM-resistant PC.

Triptolide (TP) is a promising anti-tumor candidate derived from the herb Tripterygium wilfordii, but its poor water solubility and multi-organ toxicity limit its application. Here, we developed novel nanoparticles (TP-SP@NPs) modified with dextran sulfate and RGD peptide for double-targeted delivery of TP to both tumor cells and pro-tumor macrophages in pancreatic cancer treatment. TP-SP@NPs exhibited suitable particle size (about 98 nm), good stability and controlled release performance. TP-SP@NPs showed high cellular uptake in Pan02 cells and M2 macrophages through αvβ3 integrin-RGD interaction and SR-A-DS interaction, effectively inhibiting tumor growth by triggering apoptosis of these cells. In Pan02 tumor-bearing mice, TP-SP@NPs specifically accumulated at the tumor site and efficiently decreased the number of M2 macrophages, thereby exerting better curative effect on pancreatic cancer and lower systemic toxicity as compared with TP. As a result, TP-SP@NPs had achieved selective anti-tumor effect, good biosafety and great promise in clinical application.

Pancreatic adenocarcinoma (PC) represents a prevalent and highly aggressive malignancy within the digestive system, characterized by an exceedingly poor prognosis and a dismal 5-year survival rate of below 7%. Gemcitabine (GEM) remains the cornerstone chemotherapeutic agent in the management of PC; however, the growing challenge of GEM chemoresistance, which undermines treatment efficacy, represents a significant obstacle in clinical practice. To date, no comprehensive bibliometric analysis has been undertaken to systematically explore studies on GEM resistance in the context of PC. This study aims to deliver a thorough evaluation of the research hotspots pertaining to GEM resistance in PCs.

A systematic search was conducted for articles published from 1 January 2010, to 15 December 2024, focusing on resistance studies of GEM in PC. Bibliometric analysis and visualization were performed utilizing VOSviewer and CiteSpace tools, applied to literature data extracted from the Web of Science Core Collection (WoSCC).

Between 2010 and 2024, a total of 2,689 papers were published across 472 institutions in 74 countries, reflecting a consistent upward trajectory in annual publication output. China and Fudan University emerged as the leading contributors to the research output on this topic, representing the most prolific country and institution, respectively. Giovannetti, Elisa, and Yu, Xianjun are the most prolific scholars in this field. Cancer Research stands out as the most cited and impactful journal, while research on the tumor microenvironment, targeted therapy, and circular RNA has emerged as a key focus area in recent years.

This study provides a systematic and comprehensive overview of the literature on GEM resistance in PC over the past 15 years. This analysis offers scholars critical insights into the field from a bibliometric perspective, potentially informing future studies on the development of chemotherapeutic treatments for PC.

Cancer stem cells (CSC) play a crucial role in pancreatic ductal adenocarcinoma (PDAC) progression and therapeutic resistance. However, the underlying mechanisms and potential targeted treatment strategies remain poorly understood. In this study, we employed single-cell RNA sequencing and exosomal profiling, identifying TSPAN8-enriched exosomes secreted by CSC, which are associated with poor survival rates in PDAC patients. They enhanced stemness in the surrounding non-stem cancer cells (NSCC) by activating the Sonic Hedgehog (Hh) signalling pathway. This exosomal TSPAN8-Hh signalling axis significantly increases the clonogenic ability, invasiveness, and chemoresistance of PDAC cells. Furthermore, TSPAN8-enriched exosomes promoted a higher stem cell frequency, tumourigenicity, and tumour growth rate in vivo, confirming their critical roles in PDAC malignant progression. Our findings underscore the importance of TSPAN8-enriched exosomes for CSC-NSCC communication during PDAC progression.

The purpose of the study is mainly to investigate anti proliferation of non-small cell lung cancer A549 cells and its mechanism by inhibition of CHK1 expression combined with gemcitabine. The mRNA and protein levels of genes were analyzed by RT-qPCR and Western blot, respectively. Cell viability was detected by CCK-8 assay and clone formation assay. The detection of the cell cycle was used by Annexin V/7-amino-actinomycin D apoptosis detection kit. Analysis of DNA damage was done by immunofluorescence and alkaline comet assay. The results showed that inhibition of CHK1 and gemcitabine combination significantly reduced the proliferation ability of the two cell lines. We also revealed the degradation of full-length PARP and reduced Bcl-2/Bax ratio on increased apoptosis. Inhibition of CHK1 expression leads to DNA damage, induces phosphorylation of γ-H2AX, and affects the repair of homologous recombination ability through Rad51. Mechanistically, gemcitabine increased phosphorylation-ATR and phosphorylation-CHK1, indicating activation of the DNA repair system and ATR-CHK1-CDC25A pathway. Inhibition of CHK1 resulted in increased synthesis of CDK2/Cyclin A2 and CDK2/Cyclin E1 complexes, and more cells entered the subsequent cell cycle, leading to S phase arrest and mitotic catastrophe. We identified inhibition of CHK1 as a potential treatment for NSCLC and confirmed that inhibition of this kinase could overcome acquired gemcitabine resistance.

Pancreatic cancer (PC) has high lethality due to multiple reasons, and its limited response to conventional chemotherapy like gemcitabine (GEM) is a non-negligible one. Therefore, our study introduces Chlorophyllin (CHL) as an effective therapeutic candidate to enhance the therapeutic efficacy of GEM. Our results demonstrate that the combination of CHL and GEM exhibits a significant synergistic anti-tumor effect by targeting multiple oncogenic processes in PC, including inhibiting cell proliferation, invasion, and migration, as well as inducing cell apoptosis. Further investigations of mechanism have revealed that CHL induces cuproptosis in PC cells through a multifaceted process, involving depleting cellular intracellular glutathione (GSH), increasing reactive oxygen species (ROS) levels, and subsequently upregulating the HSP70 protein in response to heightened oxidative stress. Additionally, CHL releases free Cu2+, binds to the Ferredoxin 1 (FDX1) protein, and ultimately leads to the oligomerization of Dihydrolipoamide S-Acetyltransferase (DLAT) proteins to amplify the copper toxicity within PC cells. Moreover, in vivo experiments have demonstrated that the combination of CHL and GEM effectively inhibits the growth of subcutaneously transplanted tumors while maintaining a favorable biosafety profile. In conclusion, our study identifies CHL as a potent enhancer of GEM's anti-tumor effects in PC through the induction of cuproptosis, thus providing a novel therapeutic avenue for patients with PC.

Chemotherapy remains a gold standard in cancer treatment by targeting the rapidly dividing cancer cells. However, chemoresistance is a major obstacle to successful cancer treatment, often leading to recurrence, metastasis, and high mortality. Deubiquitinases (DUBs), enzymes that remove ubiquitin and stabilize proteins, have been implicated in chemoresistance and can either promote therapeutic resistance or enhance sensitivity depending on their targets. In this review, we highlight the chemoresistance mechanisms of DUBs in various cancers, including breast, lung, liver, gastrointestinal, colorectal, ovarian, prostate, and blood cancers. Given these mechanisms, the development of DUB inhibitors has gained considerable attention in cancer therapeutics and combination therapies involving these inhibitors show potential to overcome drug resistance and improving treatment outcomes.

De novo or acquired resistance to chemotherapy is ubiquitous in pancreatic ductal adenocarcinoma (PDAC). SCO-101 is an oral compound that may counteract chemo-resistance by interacting with SRPK1, ABCG2 drug transporter, and liver enzyme UGT1A1. We first conducted preclinical experiments in paclitaxel-resistant PDAC cells to access the tumoricidal effects of SCO-101 or SRPK1-inhibitor alone or in combination with paclitaxel. Second, we enrolled 22 patients with non-resectable PDAC in a phase Ib trial to investigate safety and pharmaco-kinetics, and to establish maximum tolerated dose (MTD) by evaluation of dose-limiting toxicities (DLTs) during the first cycle of 80% dose gemcitabine (Gem) and nab-paclitaxel (Nab) together with increasing doses of SCO-101. In paclitaxel-resistant PDAC cells in vitro, a synergistic effect between SCO-101 and paclitaxel was demonstrated. In patients, daily doses for 6 days of SCO-101 resulted in a two- to threefold drug accumulation, and drug exposure was dose proportional. Treatment was well tolerated. Transiently increased blood bilirubin attributable to SCO-101 was observed in 12 cases (55%) and associated with jaundice in three patients. One and two DLTs, respectively, were observed at 150 and 250mg dosing-levels of SCO-101, and the MTD was determined to be 200 mg of SCO-101 daily for 6 days on a bi-weekly schedule together with 80% dose of Gem and Nab. Median progression-free and overall survival was 3.3 and 9.5 months, respectively. In PDAC, SCO-101 can be added to Gem and Nab with little and manageable toxicity. However, no clear added efficacy signal was observed of the combination. Trial registration number: NCT04652205 (Nov 29, 2020).

Disulfidptosis is a newly discovered formation of programmed cell death. However, the significance of disulfidptosis in pancreatic adenocarcinoma remains unclear. Our investigation aims to elucidate the significance of disulfidptosis in pancreatic ductal adenocarcinoma by integrating diverse datasets, including bulk RNA sequencing data, microarray profiles, single-cell transcriptome profiles, spatial transcriptome data, and biospecimens. Utilizing various bioinformatics tools, we screened disulfidptosis-related genes based on single-cell RNA sequencing profiles, subsequently validating them through enrichment analysis. An 8-gene disulfidptosis-related prognostic signature was established by constructing massive LASSO-Cox regression models and validated by multiple external PDAC cohorts. Evaluation methods, such as Kaplan-Meier curves, ROC curves, time-dependent ROC curves, and decision curve analysis, were employed to assess the prognostic signature's reliability. High disulfidptosis-related scores were associated with a poorer prognosis and diminished sensitivity to immune checkpoint blockade. Further investigation uncovered that the potential components of elevated DPS involve malignant tumor hallmarks, extensive interactions between myCAFs and tumor cells, and the exclusion of immune cells. Cell-cell communication analysis highlighted myCAFs' role in signaling, potentially influencing tumor cells towards increased malignancy through collagen, laminin, and FN1 signaling networks. Spatial transcriptome analysis confirmed the crosstalk between myCAFs and tumor cells. Biospecimens including 20 pairs of PDAC samples and adjacent normal tissues further demonstrated the robustness of DPS and its correlation with CAF markers. In conclusion, our study introduces a novel disulfidptosis-related signature with high efficacy in patient risk stratification, which has the ability to predict the sensitivity to immune checkpoint blockade.

Zinc oxide nanoparticles (ZnO-NPs) have gained significant attention in cancer therapy due to their unique physical and chemical properties, particularly in treating gastrointestinal (GI) cancers such as gastric, colorectal, and hepatocellular carcinoma. These nanoparticles generate reactive oxygen species (ROS) upon entering cancer cells, causing oxidative stress that leads to cellular damage, DNA fragmentation, and apoptosis. ZnO-NPs affect the expression of key proteins involved in apoptosis, including p53, Bax, and Bcl-2, which regulate cell cycle arrest and programmed cell death. Additionally, ZnO-NPs can reduce mitochondrial membrane potential, further enhancing apoptosis in cancer cells. Furthermore, ZnO-NPs inhibit cancer cell proliferation by interfering with cell cycle progression. They reduce levels of cyclins and cyclin-dependent kinases (CDKs), leading to cell cycle arrest. ZnO-NPs also exhibit anti-metastatic properties by inhibiting the migration and invasion of cancer cells through modulation of signaling pathways that affect cell adhesion and cytoskeletal dynamics. The efficacy of ZnO-NPs in overcoming chemotherapy resistance has been demonstrated by their ability to reduce the IC50 values of chemotherapeutic agents, making cancer cells more susceptible to drug-induced cell death. In this review, we summarize the mechanisms by which ZnO-NPs exert anticancer effects in GI cancers, focusing on apoptosis, cell cycle regulation, and metastasis inhibition, while also highlighting the current limitations in translating these findings into effective clinical treatments.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world, mainly because of its powerful pro-connective tissue proliferation matrix and immunosuppressive tumor microenvironment (TME), which promote tumor progression and metastasis. In addition, the extracellular matrix leads to vascular collapse, increased interstitial fluid pressure, and obstruction of lymphatic return, thereby hindering effective drug delivery, deep penetration, and immune cell infiltration. Therefore, reshaping the TME to enhance tumor perfusion, increase deep drug penetration, and reverse immune suppression has become a key therapeutic strategy. Traditional therapies for PDAC, including surgery, radiation, and chemotherapy, face significant limitations. Surgery is challenging due to tumor location and growth, while chemotherapy and radiation are hindered by the dense extracellular matrix and immunosuppressive TME. In recent years, the advancement of nanotechnology has provided new opportunities to improve drug efficacy. Nanoscale drug delivery systems (NDDSs) provide several advantages, including improved drug stability in vivo, enhanced tumor penetration, and reduced systemic toxicity. However, the clinical translation of nanotechnology in PDAC therapy faces several challenges. These include the need for precise targeting and control over drug release, potential immune responses to the nanocarriers, and the scalability and cost-effectiveness of production. This article provides an overview of the latest nanobased methods for achieving better therapeutic outcomes and overcoming drug resistance. We pay special attention to TME-targeted therapy in the context of PDAC, discuss the advantages and limitations of current strategies, and emphasize promising new developments. By emphasizing the enormous potential of NDDSs in improving the treatment outcomes of patients with PDAC, while critically discussing the limitations of traditional therapies and the challenges faced by nanotechnology in achieving clinical breakthroughs, our review paves the way for future research in this rapidly developing field.

The DNA-damaging agent Gemcitabine (GEM) is a first-line treatment for pancreatic cancer, but chemoresistance is frequently observed. Several clinical trials investigate the efficacy of GEM in combination with targeted drugs, including kinase inhibitors, but the experimental evidence for such rationale is often unclear. Here, we phenotypically screened 13 human pancreatic adenocarcinoma (PDAC) cell lines against GEM in combination with 146 clinical inhibitors and observed strong synergy for the ATR kinase inhibitor Elimusertib in most cell lines. Dose-dependent phosphoproteome profiling of four ATR inhibitors following DNA damage induction by GEM revealed a strong block of the DNA damage response pathway, including phosphorylated pS468 of CHEK1, as the underlying mechanism of drug synergy. The current work provides a strong rationale for why the combination of GEM and ATR inhibition may be useful for the treatment of PDAC patients and constitutes a rich phenotypic and molecular resource for further investigating effective drug combinations.

Pancreatic cancer (PC) presents a significant challenge in treatment efficacy due to late-stage diagnosis and chemoresistance. The effects of the combination of a selective small-molecule AHR inhibitor and gemcitabine treatmenteffectiveness in PC cells has been a focus of research. This study utilized the PC cell lines BxPC-3 and Su.86.86 to investigate the impact of AHR activity modulation on gene and protein expression related to the gemcitabine response. Assays including viability measurement, combinational index calculation, qRT-PCR, Western blot analysis, immunocytofluorescence, and clonogenic assays, were employed. Additionally, patient tissue samples were analysed for AHR, ELAVL1, and DCK levels. The results show that AHR activity modulation influenced ELAVL1 localization, DCK expression, and gemcitabine response. Inhibition of AHR activity caused synergistic effects with gemcitabine, whereas activation had an antagonistic effect. Regarding colony formation, inhibition of AHR increased gemcitabine effectiveness by 30-41%, whereas activation decreased the response by 11-28%. Patient tissue analysis revealed correlations between AHR, ELAVL1, and DCK mRNA levels and showed increased levels of AHR protein (2.2-fold) and decreased DCK protein levels (36% decrease) in tumor tissue compared to next-to-cancer tissue. These findings demonstrate the potential of AHR modulation to improve gemcitabine treatment outcomes. This study highlights the significance of AHR modulation in influencing the gemcitabine response in PC cells. By inhibiting AHR activity, cells exhibited improved gemcitabine response, offering a promising avenue for enhancing treatment efficacy. These findings suggest that AHR could serve as a target for optimizing gemcitabine treatment and potentially reducing cancer aggressiveness.

Pancreatic cancer remains one of the most lethal cancers due to late diagnosis and high chemoresistance. Despite recent progression in the development of chemotherapies, immunotherapies, and potential nanoparticles-based approaches, the success rate of therapeutic response is limited which is further compounded by cancer drug resistance. Understanding of emerging biological and molecular pathways causative of pancreatic cancer's aggressive and chemoresistance is vital to improve the effectiveness of existing therapeutics and to develop new therapies. One such under-investigated and relatively less explored area of research is documenting the effect that lipids, specifically cholesterol, and its metabolism, impose on pancreatic cancer. Dysregulated cholesterol metabolism has a profound role in supporting cellular proliferation, survival, and promoting chemoresistance and this has been well established in various other cancers. Thus, we aimed to provide an in-depth review focusing on the significance of cholesterol metabolism in pancreatic cancer and relevant genes at play, molecular processes contributing to cellular cholesterol homeostasis, and current research efforts to develop new cholesterol-targeting therapeutics. We highlight the caveats, weigh in different experimental therapeutic strategies, and provide possible suggestions for future research highlighting cholesterol's importance as a therapeutic target against pancreatic cancer resistance and cancer progression.

Circular RNAs (circRNAs) are a class of novel RNA molecules featured by single-strand covalently closed circular structure, which not only are extensively found in eukaryotes and are highly conserved, but also conduct paramount roles in the occurrence and progression of pancreatic cancer (PC) through diverse mechanisms. As recent studies have demonstrated, circRNAs typically exhibit tissue-specific and cell specific expression patterns, with strong potential as biomarkers for disease diagnosis and prognosis. On the basis of their localization and specific interactions with DNA, RNA, and proteins, circRNAs are considered to possess specific biological functions by acting as microRNA (miRNA) sponges, RNA binding protein (RBP) sponges, transcriptional regulators, molecular scaffolds and translation templates. On that account, further addressing the technical difficulties in the detection and research of circRNAs and filling gaps in their biological knowledge will definitely push ahead this comparatively young research field and bring circRNAs to the forefront of clinical practice. Thus, this review systematically summarizes the biogenesis, function, molecular mechanisms, biomarkers and therapeutic targets of circRNAs in PC.

Autophagy and the Warburg effect are two common pathways in pancreatic ductal adenocarcinoma (PDAC). To date, the reciprocal effects of these pathways have not yet been elucidated. Therefore, this study was designed to investigate the relationship between these factors in vitro and may provide therapeutic targets in the future. The Mia-Paca-2 and AsPc-1 cell lines were cultured under normal conditions. To achieve autophagy, starvation was induced by Hank's balanced salt solution (HBSS), whereas autophagy was inhibited by 3-methyladenine (3-MA). The Warburg effect is mimicked by lactic acid, and the Warburg effect is inhibited by oxamate, the main inhibitor of lactate dehydrogenase. Cell viability was checked through the MTT assay method. Autophagy was checked via evaluation of Beclin-1 via western blotting. The amount of lactic acid was also measured with a lactate dehydrogenase (LDH) assay kit. The cells were incubated with different concentrations of 3-MA, lactic acid and oxamate. The viability of AsPc-1 cells decreased, and the IC50 values were 1195 µM, 23.06 mM and 8.617 mM for 3-MA, lactic acid and oxamate, respectively. Similarly, the IC50 values of Mia-Paca-2 were 873.9 µM, 35.9 mM and 26.74 mM for 3-MA, lactic acid and oxamate, respectively. Our data revealed that starvation increased the expression of the autophagy-related protein Beclin-1 (P value < 0.05); however, 3-MA significantly reduced its expression (P value < 0.05). In addition, lactic acid alone did not affect the expression level of Beclin-1 (P value > 0.05), but oxamate treatment increased its expression (P value < 0.05). We also showed that starvation reduced lactic acid levels, but an autophagy inhibitor, 3MA, significantly increased lactic acid production (P value < 0.05). Our findings showed that lactic acid alone has no significant effect on autophagy and that oxamate induces autophagy, possibly because of caloric restriction. On the other hand, autophagy inhibits lactic acid production, whereas the inhibition of autophagy leads to increased lactic acid production.

Sonodynamic therapy (SDT) as an emerging modality for malignant tumors mainly involves in sonosensitizers and low-intensity ultrasound (US), which can safely penetrate the tissue without significant attenuation. SDT not only has the advantages including high precision, non-invasiveness, and minimal side effects, but also overcomes the limitation of low penetration of light to deep tumors. The cytotoxic reactive oxygen species can be produced by the utilization of sonosensitizers combined with US and kill tumor cells. However, the underlying mechanism of SDT has not been elucidated, and its unsatisfactory efficiency retards its further clinical application. Herein, we shed light on the main mechanisms of SDT and the types of sonosensitizers, including organic sonosensitizers and inorganic sonosensitizers. Due to the development of nanotechnology, many novel nanoplatforms are utilized in this arisen field to solve the barriers of sonosensitizers and enable continuous innovation. This review also highlights the potential advantages of nanosonosensitizers and focus on the enhanced efficiency of SDT based on nanosonosensitizers with monotherapy or synergistic therapy for deep tumors that are difficult to reach by traditional treatment, especially orthotopic cancers.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a 12% survival rate, highlighting the need for novel therapies. c-MYC overexpression, driven by upstream mutations and amplifications, reprograms tumor metabolism and promotes proliferation, migration and metastasis. This study identifies ELOVL6, a fatty acid elongase regulated by c-MYC, as a potential therapeutic target. Using PDAC mouse models and cell lines, we show that c-MYC directly upregulates ELOVL6 during tumor progression. Genetic or chemical inhibition of ELOVL6 reduces proliferation and migration by altering fatty acid composition, affecting membrane rigidity, permeability and pinocytosis. These changes increase Abraxane uptake and show a synergistic effect when combined with ELOVL6 inhibition in vitro. In vivo, ELOVL6 interference significantly suppresses tumor growth and improves Abraxane response, prolonging survival. These findings position ELOVL6 as a promising target for improving PDAC treatment outcomes.

Lactate dehydrogenase A (LDHA) can regulate tumorigenesis and cancer progression. Nevertheless, whether the regulation of LDHA is involved in the development of gemcitabine resistance in PDAC has not yet been fully elucidated. Increasing studies have shown that cancer acquired drug resistance led to treatment failure is highly attributed to the cancer stem cell (CSC) properties. Therefore, we aim to demonstrate the functions and regulatory mechanisms of LDHA on cancer stem cell (CSC) properties and gemcitabine resistance in PDAC.

We investigate the metabolite profiles by liquid chromatography-mass spectrometry between gemcitabine-resistant PDAC and parental PDAC cells. Additionally, gain-of-function and loss-of-function experiments were conducted to examine the roles of LDHA on CSC properties and gemcitabine resistance in the gemcitabine-resistant PDAC and parental PDAC cells. To investigate regulators involved in LDHA-mediated gemcitabine resistance and CSC of pancreatic cancer cells, we further used a combination of the miRNA microarray results and software predictions and confirmed that miR-4259 is a direct target of LDHA by luciferase assay. Furthermore, we constructed serial miR-4259 promoter reporters and searched for response elements using the TESS 2.0/TFSEARCH software to find the transcription factor binding site in the promoter region of miR-4259.

We observed that elevated LDHA expression significantly correlates with recurrent pancreatic cancer patients following gemcitabine treatment and with CSC properties. We further identify that FOXO3a-induced miR-4259 directly targets the 3'untranslated region of LDHA and reduced LDHA expression, leading to decreased gemcitabine resistance and a reduction in the CSC phenotypes of pancreatic cancer.

Our results demonstrated that LDHA plays a critical role in cancer stemness and gemcitabine resistance of pancreatic cancer, and indicate that targeting the FOXO3a/miR-4259/LDHA pathway might serve as a new treatment for pancreatic cancer patients with a poor response to gemcitabine chemotherapy.

Pancreatic cancer (PC) is characterized by a high relapse rate and unfavorable prognosis. Currently, the optimal treatment for PC is complete resection followed by adjuvant systemic chemotherapy. Nevertheless, tumor cell repopulation and subsequent tumor relapse and metastasis after chemotherapy result in a poor prognosis. Therefore, it is of great value to explore the potential molecular mechanisms underlying PC for developing novel treatment strategies. Herein, we aimed to investigate the potential regulatory mechanism of miR-1305 upon aerobic proliferation, metastasis, and apoptosis in PC. miR-1305 was downregulated in PC tissues and cell lines. miR-1305 overexpression prominently inhibited PC cell proliferation and metastasis promoted cell apoptosis in vitro, and alleviated PC formation in vivo. As predicted, KLF5 could directly bind to miR-1305. Silencing of KLF5 or KLF5 inhibitor (ML264) suppressed PC cell viability and cell invasion, and enhanced cell apoptosis. KLF5 restrained miR-1305 transcription and expression by binding to its promoter region. miR-1305 exerted a suppressive effect on PC cell proliferation and apoptosis via regulation of the KLF5-ERBB2 axis; KLF5 gene is a transcriptional regulator of miR-1305, promising to be a new target for the diagnosis and treatment of PC.

Chemoresistance represents a major threat to the treatment of human cancers, including cholangiocarcinoma (CHOL). Aberrant epigenetic events contribute most to the progression of CHOL and chemotherapy efficacy. PHF10, one subunit of SWI/SNF complex, expressed highly in tumours that correlated with tumorigenesis. However, the roles of PHF10 in CHOL remains unclear. Here, we utilised the bioinformatic analysis to reveal that PHF10 expressed lowly in CHOL samples relative to normal tissues. Functionally, we demonstrated that PHF10 deficiency enhanced cell proliferation, migration and self-renewal capacities of CHOL cells. PHF10 ablation further enhanced the chemoresistance of CHOL cells. The transcriptome analysis revealed that PHF10-KO could notably alter several oncogenic crosstalk, including the NF-kB signalling. As the top hit, HMGB1 mRNA expressions had the sharpest increase upon PHF10 deficiency. PHF10 coordinated with Setdb1 to mediate the H3K9me3 modifications on the HMGB1 promoter to suppress its expressions. Low PHF10 relied on HMGB1 to promote the progression of CHOL cells in vitro and in vivo. Furthermore, EZH2 mediated the H3K27me3 enrichment on the PHF10 promoter region that contributes to its low expressions. Lastly, the HMGB1 inhibitor (Glycyrrhizin) decreased proliferation rate of PHF10-deleted cells in vitro and in vivo. Targeting HMGB1 rendered PHF10low CHOL re-sensitive to chemotherapy. Collectively, this study demonstrated that PHF10 functions as a tumour suppressor in CHOL, and is a novel target to predict and overcome chemoresistance.

Pancreatic cancer is a highly fatal malignancy due to poor early detection rate and resistance to conventional therapies. This review examines the potential for liquid biopsy as a transformative technology to identify diagnostic and therapeutic targets in pancreatic cancer. Specifically, we explore emerging biomarkers such as exosomal non-coding RNAs (ncRNAs), circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs). Tumor-derived exosomes contain nucleic acid and protein that reflect the unique molecular landscape of the malignancy and can serve as an alternative diagnostic approach vs traditional biomarkers like CA19-9. Herein we highlight exosomal miRNAs, lncRNAs, and other ncRNAs alongside ctDNA and CTC-based strategies, evaluating their combined ability to improve early detection, disease monitoring and treatment response. Furthermore, the therapeutic implications of ncRNAs such as lncRNA UCA1 and miR-3960 in chemoresistance and progression are also discussed via suppression of EZH2 and PTEN/AKT pathways. Emerging therapeutic strategies that target the immune response, epithelial-mesenchymal transition (EMT) and drug resistance are explored. This review demonstrates a paradigm shift in pancreatic cancer management toward personalized, less invasive and more effective approaches.

N6‑methyladenosine (m6A) is one of the most universal, abundant and conserved types of internal post‑transcriptional modifications in eukaryotic RNA, and is involved in nuclear RNA export, RNA splicing, mRNA stability, gene expression, microRNA biogenesis and long non‑coding RNA metabolism. AlkB homologue 5 (ALKBH5) acts as a m6A demethylase to regulate a wide variety of biological processes closely associated with tumour progression, tumour metastasis, tumour immunity and tumour drug resistance. ALKBH5 serves a crucial role in human digestive system tumours, mainly through post‑transcriptional regulation of m6A modification. The present review discusses progress in the study of the m6A demethylase ALKBH5 in gastrointestinal tract cancer, summarizes the potential molecular mechanisms of ALKBH5 dysregulation in gastrointestinal tract cancer, and discusses the significance of ALKBH5‑targeted therapy, which may provide novel ideas for future clinical prognosis prediction, biomarker identification and precise treatment.

Neoadjuvant chemotherapy (NAC) can provide improved survival outcomes in pancreatic ductal adenocarcinoma (PDAC) patients who respond to treatment, but currently available biomarkers cannot reliably predict NAC response. This study aimed to determine the potential of a previously identified diagnostic and prognostic biomarker panel (i.e. Ca-125, S100A2, S100A4, Mesothelin and Ca19-9) for the monitoring of NAC-response in PDAC patients.

This single-centre, retrospective study, utilised serum from NAC treated PDAC patients to determine the levels of biomarkers by Enzyme-Linked Immunosorbent Assay (ELISA). The percentage of the tumour bed occupied by viable carcinoma (PVC) was used to divide patients into good (PVC < 50%) and poor (PVC ≥ 50%) NAC-responders. Statistical analysis was performed to measure the ability of individual biomarkers and a biomarker panel in NAC treatment response and patient survival.

Serum specimens from a total of 108 PDAC patients were assessed. Ca-125, Ca19-9 and S100A2 showed a significant positive correlation with PVC. Ca-125 demonstrated a superior ability to monitor NAC treatment response (Area under receiver operating curve (AUC): .6954) compared to the more widely used clinical biomarker, Ca19-9 (AUC: .6291). A panel of Ca-125 and Ca19-9 showed good ability to monitor NAC response in PDAC patients (AUC: .7349). Patients with high levels of both Ca-125 and Ca19-9 were shown to have the poorest overall survival (median overall survival: 17 vs. 30 months).

A serum biomarker panel of Ca-125 and Ca19-9 could be used for effective clinical management of PDAC patients undergoing NAC treatment.

Hypoxia in tumor cells is linked to increased drug resistance and more aggressive behavior. In pancreatic cancer, the tumor microenvironment is notably hypoxic and exhibits strong immunosuppressive properties. Given that immunotherapy is now approved for pancreatic cancer treatment, further understanding of how pancreatic tumor cell hypoxia influences T-cell cytotoxicityis essential.

This study examined how hypoxia affects the interaction between pancreatic tumor cells (PANC-1) and cytotoxic CD8+ T-cells.

Pancreatic tumor cells (PANC-1) were exposed to 20 cycles of chronic hypoxic conditions, each for 72 hours, followed by a re-oxygenation period for 24 hours. On cycles 10 and 20, PANC-1 conditioned media (CM) was harvested, and the hypoxic PANC-1 cells were co-cultured with either the activated cytotoxic CD8+ T-cells or with CD8+ T-cells CM. CD8+ T-cells CM was collected after five days of cell activation using anti-CD3/CD28 antibodies and interleukin-2 (IL-2). CD8+ T-cells were activated for 72 hours and then cultured with the hypoxic PANC-1 CM.

Hypoxic PANC-1 cells showed significant resistance to the lytic effect of either CD8+ T-cells co-culture or CD8+ T-cells CM treatment compared to normoxic PANC-1 cells. A significant decrease in TNF-α and IFN-γ levels was also detected. Additionally, a significant increase in IL-6, p53 and TNF-α gene expression levels was observed in PANC-1 cells treated with CD8+ T-cells CM. Moreover, IL-6 gene expression level showed a significant difference between hypoxic and normoxic PANC-1 cells. CD8+ T-cell proliferation and cytokines production were significantly higher in cells co-cultured with PANC-1 CM. However, no significant differences were observed after treatment with either hypoxic or normoxic PANC-1 CM.

Hypoxia decreases PANC-1 cells' sensitivity to cytotoxic CD8+ T-cells. Reduced tumor cell susceptibility to CD8+ T-cells was associated with increased IL-6 expression and reduced TNF-α and IFN-γ levels. Thus, cytokine dysregulation might contribute to the hypoxia-mediated resistance of pancreatic tumor cells to CD8+ T-cells.

The KRAS gene is nearly ubiquitously subjected to activating mutation in pancreatic adenocarcinomas (PDAC), occurring at a frequency of over 90% in tumors. Mutant KRAS drives sustained signaling through the MAPK pathway to affect frequently disrupted cancer phenotypes including transcription, proliferation and cell survival. Recent research has shown that PDAC tumor growth and survival required a guanine nucleotide exchange factor for RAS homolog family member A (RhoA) called GEF-H1. The GEF-H1 protein, encoded by the ARHGEF2 gene, is a microtubule-associated GEF for RhoA that promotes invasion-migration of PDAC cells via activation of RhoA. Unexpectedly, independent of its RhoGEF activity, GEF-H1 was found to potentiate MAPK signaling by scaffolding protein phosphatase 2A (PP2A) to the kinase suppressor of Ras 1 (KSR-1). In a feedback-dependent manner, enhanced MAPK activity drives expression of ARHGEF2 via regulation of transcription factors ETS and SP, and the RAS responsive element-binding protein 1 (RREB1). RREB1 a negative regulator of ARHGEF2 expression, is downregulated in PDAC cells, which permits sustained expression of GEF-H1 for PDAC tumor survival and subsequent MAPK pathway activation. Given that MAPK targeted therapies show limited clinical efficacy, highlights the need for novel targets. This review describes the unexpected complexity of GEF-H1 function leading to positive feedback that potentiates RAS-MAPK signaling and suggests inhibition of GEF-H1 as a therapeutic strategy for RAS-driven cancers.

Pancreatic adenocarcinoma (PDAC) remains one of the most lethal cancers, with limited advancements in treatment efficacy due to high rates of chemoresistance. Circulating tumor cells (CTCs) derived from liquid biopsies offer a non-invasive approach to monitoring tumor evolution and identifying molecular mechanisms of resistance. This study aims to longitudinally collect, culture, and characterize CTCs from PDAC patients to elucidate resistance mechanisms and tumor-specific gene expression profiles.

Blood samples from 10 PDAC patients were collected across different treatment stages, yielding 16 CTC cultures. Differential gene expression, pathway dysregulation, and protein-protein interaction studies were utilized, highlighting patient-specific and disease progression-associated changes. Longitudinal comparisons within five patients provided further insights into dynamic molecular changes associated with therapeutic resistance.

CTC cultures exhibited the activation of key pathways implicated in PDAC progression and resistance, including TNFα/NF-kB, hedgehog signaling, and the epithelial-to-mesenchymal transition. Longitudinal samples revealed dynamic changes in signaling pathways, highlighting upregulated mechanisms of chemoresistance, including PI3K/Akt/mTOR and TGF-β pathways. Additionally, protein-protein interaction analysis emphasized the role of the immune system in PDAC progression and therapy response. Patient-specific gene expression patterns therefore suggest potential applications for precision medicine.

This proof-of-concept study demonstrates the feasibility of longitudinally capturing and analyzing CTCs from PDAC patients. The findings provide critical insights into molecular drivers of chemoresistance and highlight the potential of CTC profiling to inform personalized therapeutic strategies. Future large-scale studies are warranted to validate these findings and further explore CTC-based approaches in PDAC management.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited treatment options. Investigating novel therapeutic targets and understanding mechanisms of chemoresistance are crucial for improving patient outcomes. This study investigated the role of CKS1B in PDAC carcinogenesis, stemness and chemoresistance, and explores the underlying mechanisms driving its upregulation. The findings may provide novel therapeutic insights and potential strategies for the treatment of PDAC. Methods: CKS1B expression was analyzed in PDAC tissues and cell lines, its impact on cell proliferation, migration, apoptosis, stemness and chemosensitivity were evaluated by using in vitro and in vivo models, and its underlying mechanistic connection to transcription factor FOXM1 was explored by using molecular biology methods. Results: CKS1B was significantly upregulated in PDAC tissues and correlated with poor patient survival. CKS1B promoted PDAC cell proliferation, migration, and inhibited apoptosis. Expression of CKS1B enhanced the stemness properties of pancreatic cancer. CKS1B knockdown sensitized PDAC cells to the treatment of gemcitabine and oxaliplatin. Mechanistically, CKS1B is transcriptionally regulated by FOXM1, establishing a novel FOXM1-CKS1B signaling axis that regulates carcinogenesis, proliferation, migration, stemness, apoptosis, and drug resistance in PDAC. Conclusions: Our findings strongly suggest that CKS1B plays a critical role in PDAC progression, stemness and chemoresistance. Targeting the FOXM1-CKS1B axis represents a promising therapeutic strategy for PDAC patients.

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest malignant tumor, with a grim 5-year overall survival rate of about 12%. As its incidence and mortality rates rise, it is likely to become the second-leading cause of cancer-related death. The radiological assessment determined the stage and management of PDAC. However, it is a highly heterogeneous disease with the complexity of the tumor microenvironment, and it is challenging to adequately reflect the biological aggressiveness and prognosis accurately through morphological evaluation alone. With the dramatic development of artificial intelligence (AI), multiparametric magnetic resonance imaging (mpMRI) using specific contrast media and special techniques can provide morphological and functional information with high image quality and become a powerful tool in quantifying intratumor characteristics. Besides, AI has been widespread in the field of medical imaging analysis. Radiomics is the high-throughput mining of quantitative image features from medical imaging that enables data to be extracted and applied for better decision support. Deep learning is a subset of artificial neural network algorithms that can automatically learn feature representations from data. AI-enabled imaging biomarkers of mpMRI have enormous promise to bridge the gap between medical imaging and personalized medicine and demonstrate huge advantages in predicting biological characteristics and the prognosis of PDAC. However, current AI-based models of PDAC operate mainly in the realm of a single modality with a relatively small sample size, and the technical reproducibility and biological interpretation present a barrage of new potential challenges. In the future, the integration of multi-omics data, such as radiomics and genomics, alongside the establishment of standardized analytical frameworks will provide opportunities to increase the robustness and interpretability of AI-enabled image biomarkers and bring these biomarkers closer to clinical practice. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 4.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly type of cancer, with an extremely low five-year overall survival rate. To date, current treatment options primarily involve various chemotherapies, which often prove ineffective and are associated with substantial toxicity. Furthermore, immunotherapies utilizing checkpoint inhibitors have shown limited efficacy in this context, highlighting an urgent need for novel therapeutic strategies. This study investigates the preclinical efficacy of an innovative targeted therapy based on antibody-cytokine fusion proteins, specifically interleukin-2 (IL-2), a pivotal driver of cell-mediated immunity, fused to L19 antibody, which selectively binds to extra domain B of fibronectin (EDB-FN1) expressed in the tumor microenvironment.

We tested the effectiveness of different immunocytokines through in vivo characterization in syngeneic C57BL/6J orthotopic mouse models of PDAC. Based on these results, we decided to focus on L19-IL2. To assess the efficacy of this immunocytokine we developed an ex-vivo immune-spheroid interaction platform derived from murine 3D pancreatic cultures, and telomerase reverse transcriptase (TERT) specific T-lymphocytes. Moreover, we evaluated the anti-cancer effect of L19-IL2 in combination with standard therapy in vivo experiments in PDAC mouse models. Tumor samples collected after the treatments were characterized for tumor infiltrating immune cell components by bulk RNA sequencing (RNA-seq) and spatial transcriptomics (Stereo-seq) analysis.

The tumor-targeted L19-IL2 fusion protein demonstrated potent, dose-dependent anti-tumor activity in mice with pancreatic tumors resistant to standard chemotherapy. Spatial Transcriptomics (ST) and RNA-seq analyses indicated that L19-IL2 treatment induced a significant influx of immune cells into the tumor microenvironment, with these cells expressing activation markers like granzymes, perforins, and the IL-2 receptors.

Our results demonstrated that L19-IL2 enhances immune infiltration and cytotoxicity, remodeling the "cold" tumor microenvironment (TME) in PDAC. This innovative antibody-cytokine fusion protein improves therapeutic outcomes, paving the way for novel targeted treatment strategies in PDAC.

A highly aggressive neoplastic disease, pancreatic ductal adenocarcinoma (PDAC) is documented as the third chief cause of cancer-associated mortality in both sexes combined in the United States. For decades, gemcitabine-based chemotherapy has been embraced as a cornerstone drug for the treatment of PDAC. However, there have been several unsolved problems, including cytotoxicity, and chemoresistance. Gemcitabine efficacy was attributed to the attenuation of ribonucleotide reductase subunit-M1 (RRM1). Overexpression of RRM1 in PDAC is highly correlated with gemcitabine resistance and reduced gemcitabine sensitivity, resulting in a poor survival rate even after gemcitabine treatment. Moreover, the status of TP53, a tumor suppressor gene, assumes a decisive role in the response of PDAC to gemcitabine. Therefore, targeting RRM1 and P53 might be a therapeutic strategy for strengthening gemcitabine efficacy and cytotoxicity against PDAC. Alpinumisoflavone (AIF) is a prenylated isoflavone originated in Cudrania tricuspidate with versatile bioactive properties, including anticancer activity. However, there was no report whether AIF can exert anticancer effect and exhibit synergistic effect with gemcitabine against PDAC. Therefore, the anticancer properties of AIF were assessed with PANC-1 and MIA PaCa-2. In addition, synergism between AIF and gemcitabine were analyzed. Moreover, the contribution of P53 and RRM1 expression to gemcitabine resistance was assessed by comparing their protein levels in PDAC cells and normal pancreatic cells. The interactions of AIF with RRM1 protein were confirmed by molecular docking and dynamics simulation. Therefore, AIF enhances gemcitabine efficacy against PDAC through the regulation of P53 and RRM1.

Most pancreatic cancer patients are diagnosed at advanced stages, with poor survival rates and drug resistance making pancreatic cancer one of the highest causes of cancer death in the UK. Understanding the underlying mechanism behind its carcinogenesis, metastasis and drug resistance has become an essential task for researchers. We have discovered that a well-established tumour suppressor, EPLIN, has an oncogenic rather than suppressive role in pancreatic cancer. Notably, upregulation of EPLIN was observed in pancreatic cancer samples compared to normal samples at RNA and protein levels. Moreover, the presence of EPLIN resulted in poor clinical outcomes in patients. We also report that inhibition of EPLIN led to reduced cellular growth and migration in pancreatic cancer cells. EPLIN regulates expression and phosphorylation levels of several key players in MAPK and PIK3CA-AKT signalling pathways, as well as key contributors of EMT. Furthermore, EPLIN mediates the inhibitory ability PIK3 kinases, MEK and ERK inhibitors have on cell migration. EPLIN was also found to have an impact on pancreatic cancer cells response to chemotherapeutic and EGFR/HER2 targeted therapeutic agents, namely gemcitabine, fluorouracil (5FU) and neratinib (Nerlynx).

This study examined the response to cisplatin in BxPC-3, Mia-Paca-2, PANC-1, and YAPC pancreatic cancer lines with different genotypic and phenotypic characteristics, and the mechanisms associated with their resistance. BxPC-3 and MIA-PaCa-2 cell lines were the most sensitive to cisplatin, while YAPC and PANC-1 were more resistant. Consistently, in cisplatin-treated BxPC-3 cells, the cleavage patterns of pro-caspase-9, -7, -3, and PARP-1 demonstrated that they were more sensitive than YAPC cells. The autophagic pathway, promoting cisplatin resistance, was active in BxPC-3 cells, as demonstrated by the time-dependent conversion of LC3-I to LC3-II, whereas it was not activated in YAPC cells. In cisplatin-treated BxPC-3 cells, Bcl-2 decreased, while Beclin-1, Atg-3, and Atg-5 increased along with JNK1/2 phosphorylation. Basal levels of phosphorylated ERK1/2 in each cell line were positively correlated with cisplatin IC50 values, and cisplatin caused the activation of ERK1/2 in BxPC-3 and YAPC cells. Furthermore, ERK1/2 pharmacological inactivation increased cisplatin lethality in both BxPC-3 and YAPC cells, suggesting that p-ERK1/2 may be related to cisplatin resistance of PDAC cells. Different mechanisms and strategies are generally required to acquire drug resistance. Here, we partially explain the other response to cisplatin of BxPC-3 and YAPC cell lines by relating it to the role of ERK pathway.