Barriers and opportunities for gemcitabine in pancreatic cancer therapy

Abstract

Pancreatic ductal adenocarcinoma (PDA) has become one of the leading causes of cancer-related deaths across the world. A lack of durable responses to standard-of-care chemotherapies renders its treatment particularly challenging and largely contributes to the devastating outcome. Gemcitabine, a pyrimidine antimetabolite, is a cornerstone in PDA treatment. Given the importance of gemcitabine in PDA therapy, extensive efforts are focusing on exploring mechanisms by which cancer cells evade gemcitabine cytotoxicity, but strategies to overcome them have not been translated into patient care. Here, we will introduce the standard treatment paradigm for patients with PDA, highlight mechanisms of gemcitabine action, elucidate gemcitabine resistance mechanisms, and discuss promising strategies to circumvent them.

Keywords: chemoresistance; gemcitabine; metabolism; pancreatic cancer; tumor microenvironment.

Graphical abstract

Figure 1.

Treatment paradigm in pancreatic cancer. Recommended treatment approach for patients with PDA based on cancer stage. Patients are preferentially evaluated in a multidisciplinary tumor conference and clinical trials are encouraged whenever possible. Early testing for actionable genomic alterations is recommended for patients with advanced PDA. BSC, best supportive care; ECOG, Eastern Cooperative Oncology Group; 5-FU, 5-fluorouracil; Gem, gemcitabine; LV, leucovorin; (m)FOLFIRINOX, modified FOLFIRINOX (5-fluorouracil, irinotecan, leucovorin, oxaliplatin); nab, nanoparticle albumin-bound; nal, nanoliposomal; PDA, pancreatic adenocarcinoma. Image created with BioRender and published with permission.

Figure 2.

Mechanisms of gemcitabine action. The prodrug dFdC is transported through the cell membrane by nucleoside transporters and phosphorylated to its active diphosphate (dFdCDP) and triphosphate forms (dFdCTP). dFdCTP is incorporated into the DNA, ultimately terminating DNA synthesis. dFdCMP is dephosphorylated to dFdC via 5′nucleotidase, dFdC and dFdCMP are inactivated by CDA and DCTD. As self-potentiation mechanisms, binding of dFdCDP inactivates RR and thereby eliminates competing dCTP pools, and binding of dFdCTP inactivates CDA. CDA, cytidine deaminase; CDP, cytidine-5′-diphosphate; dCDP, 2′-deoxycytidine-5′-diphosphate; dCK, deoxycytidine kinase; DCTD, deoxycytidylate deaminase; dCTP, 2′-deoxycytidine-5′-triphosphate; dFdC, 2′,2′-difluoro-2′-deoxycytidine; dFdCDP, 2′,2′-difluoro-2′-deoxycytidine-5′-diphosphate; dFdCMP, 2′,2′-difluoro-2′-deoxycytidine-5′-monophosphate; dFdCTP, 2′-difluoro-2′-deoxycytidine-5′-triphosphate; dFdU, 2′-deoxy-2′,2′-difluorouridine, dFdUMP, 2′-deoxy-2′,2′-difluorouridine monophosphate; hCNT3, human concentrative nucleoside transporter 3; hENT1, human equilibrative nucleoside transporter 1; NDPK, nucleotide diphosphate kinase; NMPK, nucleotide monophosphate kinase; 5′NT, 5′ nucleotidase; RR, ribonucleotide reductase. Image created with BioRender and published with permission.

Figure 3.

Cell-intrinsic and noncell autonomous gemcitabine resistance mechanisms. A: cell-intrinsic mechanisms that render cancer cells less impacted by gemcitabine. Gemcitabine uptake is reduced by downregulation of hENTs; gemcitabine activation is directly inhibited by downregulation of dCK and indirectly by upregulation of RR and glucose uptake, which increases competing nucleic acid pools; gemcitabine detoxification is enhanced by upregulation of CDA. Activation of macropinocytosis and autophagy provide nutrients and promote immune evasion by degrading MHC-I molecules. B: resistance mechanisms promoted by the surrounding nonmalignant cells. CAFs and TAMs release deoxycytidine, which outcompetes gemcitabine uptake through dCK. TAMs-induced upregulation of CDA and bacterial CDA detoxify gemcitabine. CAFs produce abundant ECM, which generates high interstitial pressure, vascular collapse, and hypoxia, limiting the delivery of gemcitabine to cancer cells. Red arrows indicate up- or downregulation. CAFs, cancer-associated fibroblasts; CDA, cytidine deaminase; dCK, deoxycytidine kinase; ECM, extracellular matrix; hENT1, human equilibrative nucleoside transporter 1; PPP, pentose phosphate pathway; RR, ribonucleotide reductase; TAMs, tumor-associated macrophages. Image created with BioRender and published with permission.