Systematic exploration of the underlying mechanism of gemcitabine resistance in pancreatic adenocarcinoma

Abstract

Resistance to gemcitabine is the main challenge of chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Hence, the development of a response signature to gemcitabine is essential for precision therapy of PDAC. However, existing quantitative signatures of gemcitabine are susceptible to batch effects and variations in sequencing platforms. Therefore, based on within‐sample relative expression ordering of pairwise genes, we developed a transcriptome‐based gemcitabine signature consisting of 28 gene pairs (28‐GPS) that could predict response to gemcitabine for PDAC at the individual level. The 28‐GPS was superior to previous quantitative signatures in terms of classification accuracy and prognostic performance. Resistant samples classified by 28‐GPS showed poorer overall survival, higher genomic instability, lower immune infiltration, higher metabolic level and higher‐fidelity DNA damage repair compared with sensitive samples. In addition, we found that gemcitabine combined with phosphoinositide 3‐kinase (PI3K) inhibitor may be an alternative treatment strategy for PDAC. Single‐cell analysis revealed that cancer cells in the same PDAC sample showed both the characteristics of sensitivity and resistance to gemcitabine, and the activation of the TGFβ signalling pathway could promote progression of PDAC. In brief, 28‐GPS could robustly determine whether PDAC is resistant or sensitive to gemcitabine, and may be an auxiliary tool for clinical treatment.

Bulk anda single-cell transcriptome profiling reveals the molecular characteristics of T cell-mediated tumor killing in pancreatic cancer

“…8B ). Enhanced communication from epithelial cells to neighboring cells was detected in the TRGscore-high profiles, including NAMPT-(ITGA5+ITGB1), MIF-(CD74 + CD44), MIF-(CD74+CXCR4), ANGPTL4-SDC2, ANGPTL4-CDH11, and ANGPTL4-(ITGA5+ITGB1), which have the potential to promote tumor spread, growth, and evasion of the immune system [ [54] , [55] , [56] , [57] , [58] ]. In conclusion, these results favor the negative relationship between the TRGscore and favorable outcomes and immune activity.…”

Hepatic myofibroblasts exert immunosuppressive effects independent of the immune checkpoint regulator PD-L1 in liver metastasis of pancreatic ductal adenocarcinoma

“…However, although Gemcitabine is one of the first-line therapies for PDAC patients, it only slightly prolongs the overall survival ( 50 ). One important reason for this is the often intrinsic or acquired resistance of PDAC cells which can be also seen in PDAC cell lines ( 51 ). Accordingly, PancTu1 cells have been described as chemoresistant, as apoptosis could not or only slightly be induced by Gemcitabine ( 52 ).…”

Novel silicene-mesoporous silica nanoparticles conjugated gemcitabine induced cellular apoptosis via upregulating NF-κB p65 nuclear translocation suppresses pancreatic cancer growth in vitro and in vivo

“…Firstly, within the distinctive tumor microenvironment of pancreatic cancer, a dense fibrous interstitium is formed by extracellular matrices such as collagen fibers and hyaluronic acid [2].This unique environment renders pancreatic tumors highly resistant to conventional therapeutic approaches, namely the gemcitabine-based therapies [3,4]. As an antimetabolite and analog of deoxycytidine nucleoside, Gemcitabine exerts its anti-cancer properties by impeding the synthesis of DNA [5].…”

“…However, the therapeutic response rate remains 22%-35% due to the high resistance of the pancreatic tumor [5,6]. Factors contributing to this resistance include a hypoxic and poorly vascularized mesenchymal barrier [7], impeding the effective delivery of radiotherapeutic or chemotherapeutic agents into the tumor tissue during systemic administration and inevitably causing severe side effects on normal tissues.…”