The challenge of drug resistance in pancreatic ductal adenocarcinoma:a current overview

Pancreatic ductal adenocarcinoma(PDAC)has one of the highest mortality rates among all cancer types.Its delayed diagnosis precludes curative resection,thus most of the current therapies against PDAC are based on chemo-and radiotherapy.Unfortunately,these strategies are insufficient to improve its poor prognosis.Despite the advances made in chemotherapy(e.g.nab-paclitaxel and gemcitabine),many patients with PDAC are unable to benefit from them due to the rapid development of drug resistance.Currently,more than 165 genes have been found to be implicated in drug resistance of pancreatic tumors,including different integrins,mucins,NF-κB,RAS and CXCR4.Moreover,drug resistance in PDAC is thought to be mediated by the modulation of miRNAs(e.g.miRNA-21,miRNA-145 and miRNA-155),which regulate genes that participate in cell proliferation,invasion and metastasis.Finally,cancer stem cells are intimately related to drug resistance in PDAC due to their ability to overexpress ABC genes-involved in drug transport-,and enzymes such as aldehyde dehydrogenases-implicated in cellular drug metabolism-and poly(ADP-ribose)polymerases-involved in drug-induced DNA damage repair.Understanding the mechanisms involved in drug resistance will contribute to the development of efficient therapeutic strategies and to improve the prognosis of patients with PDAC.

Liquid biopsy approach to pancreatic cancer

Pancreatic cancer(PC)continues to pose a major clinical challenge.There has been little improvement in patient survival over the past few decades,and it is projected to become the second leading cause of cancer mortality by 2030.The dismal 5-year survival rate of less than 10%after the diagnosis is attributable to the lack of early symptoms,the absence of specific biomarkers for an early diagnosis,and the inadequacy of available chemotherapies.Most patients are diagnosed when the disease has already metastasized and cannot be treated.Cancer interception is vital,actively intervening in the malignization process before the development of a full-blown advanced tumor.An early diagnosis of PC has a dramatic impact on the survival of patients,and improved techniques are urgently needed to detect and evaluate this disease at an early stage.It is difficult to obtain tissue biopsies from the pancreas due to its anatomical position;however,liquid biopsies are readily available and can provide useful information for the diagnosis,prognosis,stratification,and follow-up of patients with PC and for the design of individually tailored treatments.The aim of this review was to provide an update of the latest advances in knowledge on the application of carbohydrates,proteins,cell-free nucleic acids,circulating tumor cells,metabo-lome compounds,exosomes,and platelets in blood as potential biomarkers for PC,focusing on their clinical relevance and potential for improving patient outcomes.