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Cited by 150Pancreatic and Hepatic Oncology ResearchPancreatitis Pathology and TreatmentCancer, Lipids, and Metabolism

Barriers and opportunities for gemcitabine in pancreatic cancer therapy

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Beutel, Alica K., Halbrook, Christopher J.·2023·American Journal of Physiology-Cell Physiology
DOI 10.1152/ajpcell.00331.2022PMC PMC9925166
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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.

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  • These anti-PDAC combinations fail to achieve complete remission and are associated with high toxicities and a high degree of intrinsic or acquired resistance due to the PDAC TME.

    “these combinations fail to achieve complete remission and they are associated with high toxicities and a high degree of intrinsic or acquired resistance due to the PDAC TME [55]”

    From Pyrvinium Pamoate Alone and With Gemcitabine Exhibits Anti‐Pancreatic Cancer Activity in <scp>2D</scp> and <scp>3D</scp> Cell Culture Models (2024) · cites this paper as [55]

    The Summary and the section on noncell-autonomous chemoresistance say that the PDAC tumor microenvironment contributes to gemcitabine resistance; the resectable-tumors section also reports high relapse rates after treatment. The paper does not establish that the combinations uniformly fail to achieve complete remission or have high toxicity. Its gemcitabine-therapy section instead describes gemcitabine as generally tolerable, and the Summary identifies cell-intrinsic mechanisms as another source of resistance. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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  1. [1]Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin 72: 7– 33, 2022. doi: 10.3322/caac.21708. 35020204 · DOI · Paper page
  2. [2]Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15: 2403– 2413, 1997. doi: 10.1200/JCO.1997.15.6.2403. 9196156 · DOI
  3. [3]Glimelius B, Hoffman K, Sjödén PO, Jacobsson G, Sellström H, Enander LK, Linné T, Svensson C. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 7: 593– 600, 1996. doi: 10.1093/oxfordjournals.annonc.a010676. 8879373 · DOI
  4. [4]Evans DB. What makes a pancreatic cancer resectable? Am Soc Clin Oncol Educ Book 38: 300– 305, 2018. doi: 10.1200/EDBK_200861. 30231408 · DOI
  5. [6]Isaji S, Mizuno S, Windsor JA, Bassi C, Fernández-Del Castillo C, Hackert T, Hayasaki A, Katz MHG, Kim S-W, Kishiwada M, Kitagawa H, Michalski CW, Wolfgang CL. International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017. Pancreatology 18: 2– 11, 2018. doi: 10.1016/j.pan.2017.11.011. 29191513 · DOI
  6. [8]Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Buchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet 389: 1011– 1024, 2017. doi: 10.1016/S0140-6736(16)32409-6. 28129987 · DOI
  7. [9]Versteijne E, Suker M, Groothuis K, Akkermans-Vogelaar JM, Besselink MG, Bonsing BA, Buijsen J, Busch OR, Creemers G-JM, van Dam RM, Eskens FALM, Festen S, de Groot JWB, Groot Koerkamp B, de Hingh IH, Homs MYV, van Hooft JE, Kerver ED, Luelmo SAC, Neelis KJ, Nuyttens J, Paardekooper GMRM, Patijn GA, van der Sangen MJC, de Vos-Geelen J, Wilmink JW, Zwinderman AH, Punt CJ, van Eijck CH, van Tienhoven G; Dutch Pancreatic Cancer Group. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the Dutch randomized phase III PREOPANC trial. J Clin Oncol 38: 1763– 1773, 2020. doi: 10.1200/JCO.19.02274. 32105518 PMC8265386 · DOI
  8. [10]Gemenetzis G, Groot VP, Blair AB, Laheru DA, Zheng L, Narang AK, Fishman EK, Hruban RH, Yu J, Burkhart RA, Cameron JL, Weiss MJ, Wolfgang CL, He J. Survival in locally advanced pancreatic cancer after neoadjuvant therapy and surgical resection. Ann Surg 270: 340– 347, 2019. doi: 10.1097/SLA.0000000000002753. 29596120 PMC6985003 · DOI
  9. [12]Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369: 1691– 1703, 2013. doi: 10.1056/NEJMoa1304369. 24131140 PMC4631139 · DOI · Paper page
  10. [13]Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul J-L, Gourgou-Bourgade S, La Fouchardière C. D, Bennouna J, Bachet J-B, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364: 1817– 1825, 2011. doi: 10.1056/NEJMoa1011923. 21561347 · DOI · Paper page
  11. [14]Sohal DPS, Kennedy EB, Cinar P, Conroy T, Copur MS, Crane CH, Garrido-Laguna I, Lau MW, Johnson T, Krishnamurthi S, Moravek C, O'Reilly EM, Philip PA, Pant S, Shah MA, Sahai V, Uronis HE, Zaidi N, Laheru D. Metastatic pancreatic cancer: ASCO Guideline Update. J Clin Oncol. In Press. doi: 10.1200/JCO.20.01364. PMC12974607 32755482 · DOI
  12. [16]Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer 47: 1676– 1681, 2011. doi: 10.1016/j.ejca.2011.04.011. 21565490 · DOI
  13. [17]Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol 32: 2423– 2429, 2014. doi: 10.1200/JCO.2013.53.6995. 24982456 · DOI
  14. [18]de Jesus VHF, Camandaroba MPG, Calsavara VF, Riechelmann RP. Systematic review and meta-analysis of gemcitabine-based chemotherapy after FOLFIRINOX in advanced pancreatic cancer. Ther Adv Med Oncol 12: 1758835920905408, 2020. doi: 10.1177/1758835920905408. 32165927 PMC7052451 · DOI
  15. [21]Pokataev I, Fedyanin M, Polyanskaya E, Popova A, Agafonova J, Menshikova S, Tryakin A, Rumyantsev A, Tjulandin S. Efficacy of platinum-based chemotherapy and prognosis of patients with pancreatic cancer with homologous recombination deficiency: comparative analysis of published clinical studies. ESMO Open 5: e000578, 2020. doi: 10.1136/esmoopen-2019-000578. 33551067 PMC7003386 · DOI
  16. [22]Toschi L, Finocchiaro G, Bartolini S, Gioia V, Cappuzzo F. Role of gemcitabine in cancer therapy. Future Oncol 1: 7– 17, 2005. doi: 10.1517/14796694.1.1.7. 16555971 · DOI
  17. [23]Sousa Cavalcante LD, Monteiro G. Gemcitabine: metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer. Eur J Pharmacol 741: 8– 16, 2014. doi: 10.1016/j.ejphar.2014.07.041. 25084222 · DOI
  18. [24]Mini E, Nobili S, Caciagli B, Landini I, Mazzei T. Cellular pharmacology of gemcitabine. Ann Oncol 17 Suppl 5: v7– v12, 2006. doi: 10.1093/annonc/mdj941. 16807468 · DOI · Paper page
  19. [25]Hamed SS, Straubinger RM, Jusko WJ. Pharmacodynamic modeling of cell cycle and apoptotic effects of gemcitabine on pancreatic adenocarcinoma cells. Cancer Chemother Pharmacol 72: 553– 563, 2013. doi: 10.1007/s00280-013-2226-6. 23835677 PMC3777243 · DOI
  20. [26]Patzak MS, Kari V, Patil S, Hamdan FH, Goetze RG, Brunner M, Gaedcke J, Kitz J, Jodrell DI, Richards FM, Pilarsky C, Gruetzmann R, Rümmele P, Knösel T, Hessmann E, Ellenrieder V, Johnsen SA, Neesse A. Cytosolic 5′-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolites. EBioMedicine 40: 394– 405, 2019. doi: 10.1016/j.ebiom.2019.01.037. 30709769 PMC6413477 · DOI
  21. [27]Morinaga S, Nakamura Y, Watanabe T, Mikayama H, Tamagawa H, Yamamoto N, Shiozawa M, Akaike M, Ohkawa S, Kameda Y, Miyagi Y. Immunohistochemical analysis of human equilibrative nucleoside transporter-1 (hENT1) predicts survival in resected pancreatic cancer patients treated with adjuvant gemcitabine monotherapy. Ann Surg Oncol 19 Suppl 3: S558– S564, 2012. doi: 10.1245/s10434-011-2054-z. 21913012 · DOI
  22. [28]Sinn M, Riess H, Sinn BV, Stieler JM, Pelzer U, Striefler JK, Oettle H, Bahra M, Denkert C, Bläker H, Lohneis P. Human equilibrative nucleoside transporter 1 expression analysed by the clone SP 120 rabbit antibody is not predictive in patients with pancreatic cancer treated with adjuvant gemcitabine—results from the CONKO-001 trial. Eur J Cancer 51: 1546– 1554, 2015. doi: 10.1016/j.ejca.2015.05.005. 26049689 · DOI
  23. [29]Saiki Y, Yoshino Y, Fujimura H, Manabe T, Kudo Y, Shimada M, Mano N, Nakano T, Lee Y, Shimizu S, Oba S, Fujiwara S, Shimizu H, Chen N, Nezhad ZK, Jin G, Fukushige S, Sunamura M, Ishida M, Motoi F, Egawa S, Unno M, Horii A. DCK is frequently inactivated in acquired gemcitabine-resistant human cancer cells. Biochem Biophys Res Commun 421: 98– 104, 2012. doi: 10.1016/j.bbrc.2012.03.122. 22490663 · DOI
  24. [30]Ohhashi S, Ohuchida K, Mizumoto K, Fujita H, Egami T, Yu J, Toma H, Sadatomi S, Nagai E, Tanaka M. Down-regulation of deoxycytidine kinase enhances acquired resistance to gemcitabine in pancreatic cancer. Anticancer Res 28: 2205– 2212, 2008. 18751396
  25. [31]Maréchal R, Mackey JR, Lai R, Demetter P, Peeters M, Polus M, Cass CE, Salmon I, Devière J, van Laethem J-L. Deoxycitidine kinase is associated with prolonged survival after adjuvant gemcitabine for resected pancreatic adenocarcinoma. Cancer 116: 5200– 5206, 2010. doi: 10.1002/cncr.25303. 20669326 · DOI
  26. [32]Nakahira S, Nakamori S, Tsujie M, Takahashi Y, Okami J, Yoshioka S, Yamasaki M, Marubashi S, Takemasa I, Miyamoto A, Takeda Y, Nagano H, Dono K, Umeshita K, Sakon M, Monden M. Involvement of ribonucleotide reductase M1 subunit overexpression in gemcitabine resistance of human pancreatic cancer. Int J Cancer 120: 1355– 1363, 2007. doi: 10.1002/ijc.22390. 17131328 · DOI
  27. [33]Han QL, Zhou YH, Lyu Y, Yan H, Dai GH. Effect of ribonucleotide reductase M1 expression on overall survival in patients with pancreatic cancer receiving gemcitabine chemotherapy: a literature-based meta-analysis. J Clin Pharm Ther 43: 163– 169, 2018. doi: 10.1111/jcpt.12655. 29214667 · DOI
  28. [34]Shukla SK, Purohit V, Mehla K, Gunda V, Chaika NV, Vernucci E, et al. MUC1 and HIF-1alpha signaling crosstalk induces anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer. Cancer Cell 32: 71– 87.e7, 2017. doi: 10.1016/j.ccell.2017.06.004. 28697344 PMC5533091 · DOI
  29. [35]Serdjebi C, Seitz J-F, Ciccolini J, Duluc M, Norguet E, Fina F, Lacarelle B, Ouafik L, Dahan L. Rapid deaminator status is associated with poor clinical outcome in pancreatic cancer patients treated with a gemcitabine-based regimen. Pharmacogenomics 14: 1047– 1051, 2013. doi: 10.2217/pgs.13.93. 23837479 · DOI
  30. [36]Ciccolini J, Dahan L, André N, Evrard A, Duluc M, Blesius A, Yang C, Giacometti S, Brunet C, Raynal C, Ortiz A, Frances N, Iliadis A, Duffaud F, Seitz J-F, Mercier C. Cytidine deaminase residual activity in serum is a predictive marker of early severe toxicities in adults after gemcitabine-based chemotherapies. J Clin Oncol 28: 160– 165, 2010. doi: 10.1200/JCO.2009.24.4491. 19933910 · DOI
  31. [37]Frese KK, Neesse A, Cook N, Bapiro TE, Lolkema MP, Jodrell DI, Tuveson DA. nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov 2: 260– 269, 2012. doi: 10.1158/2159-8290.CD-11-0242. 22585996 PMC4866937 · DOI
  32. [38]Tadros S, Shukla SK, King RJ, Gunda V, Vernucci E, Abrego J, Chaika NV, Yu F, Lazenby AJ, Berim L, Grem J, Sasson AR, Singh PK. De novo lipid synthesis facilitates gemcitabine resistance through endoplasmic reticulum stress in pancreatic cancer. Cancer Res 77: 5503– 5517, 2017. doi: 10.1158/0008-5472.CAN-16-3062. 28811332 PMC5645242 · DOI
  33. [41]Yamamoto K, Venida A, Yano J, Biancur DE, Kakiuchi M, Gupta S, Sohn ASW, Mukhopadhyay S, Lin EY, Parker SJ, Banh RS, Paulo JA, Wen KW, Debnath J, Kim GE, Mancias JD, Fearon DT, Perera RM, Kimmelman AC. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature 581: 100– 105, 2020. doi: 10.1038/s41586-020-2229-5. 32376951 PMC7296553 · DOI · Paper page
  34. [42]Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 15: 178– 196, 2014. doi: 10.1038/nrm3758. 24556840 PMC4240281 · DOI · Paper page
  35. [43]Ribatti D, Tamma R, Annese T. Epithelial-mesenchymal transition in cancer: a historical overview. Transl Oncol 13: 100773, 2020. doi: 10.1016/j.tranon.2020.100773. 32334405 PMC7182759 · DOI
  36. [44]Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL, Gallick GE, Logsdon CD, McConkey DJ, Choi W. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res 69: 5820– 5828, 2009. doi: 10.1158/0008-5472.CAN-08-2819. 19584296 PMC4378690 · DOI
  37. [45]Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, Wu C-C, LeBleu VS, Kalluri R. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527: 525– 530, 2015. doi: 10.1038/nature16064. 26560028 PMC4849281 · DOI
  38. [46]Güngör C, Zander H, Effenberger KE, Vashist YK, Kalinina T, Izbicki JR, Yekebas E, Bockhorn M. Notch signaling activated by replication stress-induced expression of midkine drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer. Cancer Res 71: 5009– 5019, 2011. doi: 10.1158/0008-5472.CAN-11-0036. 21632553 · DOI
  39. [47]Chen C, Zhao S, Karnad A, Freeman JW. The biology and role of CD44 in cancer progression: therapeutic implications. J Hematol Oncol 11: 64, 2018. doi: 10.1186/s13045-018-0605-5. 29747682 PMC5946470 · DOI
  40. [48]Makena MR, Ranjan A, Thirumala V, Reddy AP. Cancer stem cells: road to therapeutic resistance and strategies to overcome resistance. Biochim Biophys Acta Mol Basis Dis 1866: 165339, 2020. doi: 10.1016/j.bbadis.2018.11.015. 30481586 · DOI
  41. [49]Chen C, Zhao S, Zhao X, Cao L, Karnad A, Kumar AP, Freeman JW. Gemcitabine resistance of pancreatic cancer cells is mediated by IGF1R dependent upregulation of CD44 expression and isoform switching. Cell Death Dis 13: 682, 2022. doi: 10.1038/s41419-022-05103-1. 35931675 PMC9355957 · DOI
  42. [50]Novak D, Hüser L, Elton JJ, Umansky V, Altevogt P, Utikal J. SOX2 in development and cancer biology. Semin Cancer Biol 67: 74– 82, 2020. doi: 10.1016/j.semcancer.2019.08.007. 31412296 · DOI
  43. [51]Jia Y, Gu D, Wan J, Yu B, Zhang X, Chiorean EG, Wang Y, Xie J. The role of GLI-SOX2 signaling axis for gemcitabine resistance in pancreatic cancer. Oncogene 38: 1764– 1777, 2019. doi: 10.1038/s41388-018-0553-0. 30382189 PMC6408295 · DOI
  44. [52]Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res 18: 4266– 4276, 2012. doi: 10.1158/1078-0432.CCR-11-3114. 22896693 PMC3442232 · DOI · Paper page
  45. [53]Halbrook CJ, Di Pasca Magliano M, Lyssiotis CA. Tumor cross-talk networks promote growth and support immune evasion in pancreatic cancer. Am J Physiol Gastrointest Liver Physiol 315: G27– G35, 2018. doi: 10.1152/ajpgi.00416.2017. 29543507 PMC6109710 · DOI
  46. [54]Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 17: 559– 572, 2017. doi: 10.1038/nri.2017.49. 28555670 PMC5731833 · DOI
  47. [55]Dalin S, Sullivan MR, Lau AN, Grauman-Boss B, Mueller HS, Kreidl E, Fenoglio S, Luengo A, Lees JA, Vander Heiden MG, Lauffenburger DA, Hemann MT. Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance. Cancer Res 79: 5723– 5733, 2019. doi: 10.1158/0008-5472.CAN-19-0960. 31484670 PMC7357734 · DOI · Paper page
  48. [56]Hesler RA, Huang JJ, Starr MD, Treboschi VM, Bernanke AG, Nixon AB, McCall SJ, White RR, Blobe GC. TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3. Carcinogenesis 37: 1041– 1051, 2016. doi: 10.1093/carcin/bgw093. 27604902 PMC5091039 · DOI
  49. [57]Ireland L, Santos A, Ahmed MS, Rainer C, Nielsen SR, Quaranta V, Weyer-Czernilofsky U, Engle DD, Perez-Mancera PA, Coupland SE, Taktak A, Bogenrieder T, Tuveson DA, Campbell F, Schmid MC, Mielgo A. Chemoresistance in pancreatic cancer is driven by stroma-derived insulin-like growth factors. Cancer Res 76: 6851– 6863, 2016. doi: 10.1158/0008-5472.CAN-16-1201. 27742686 PMC5321488 · DOI
  50. [58]Halbrook CJ, Pontious C, Kovalenko I, Lapienyte L, Dreyer S, Lee H-J, Thurston G, Zhang Y, Lazarus J, Sajjakulnukit P, Hong HS, Kremer DM, Nelson BS, Kemp S, Zhang L, Chang D, Biankin A, Shi J, Frankel TL, Crawford HC, Morton JP, Di Pasca Magliano M, Lyssiotis CA. Macrophage-released pyrimidines inhibit gemcitabine therapy in pancreatic cancer. Cell Metab 29: 1390– 1399.e6, 2019. doi: 10.1016/j.cmet.2019.02.001. 30827862 PMC6602533 · DOI · Paper page
  51. [59]Weizman N, Krelin Y, Shabtay-Orbach A, Amit M, Binenbaum Y, Wong RJ, Gil Z. Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. Oncogene 33: 3812– 3819, 2014. doi: 10.1038/onc.2013.357. 23995783 · DOI · Paper page
  52. [60]Banh RS, Biancur DE, Yamamoto K, Sohn ASW, Walters B, Kuljanin M, Gikandi A, Wang H, Mancias JD, Schneider RJ, Pacold ME, Kimmelman AC. Neurons release serine to support mRNA translation in pancreatic cancer. Cell 183: 1202– 1218.e25, 2020. doi: 10.1016/j.cell.2020.10.016. 33142117 PMC8100789 · DOI · Paper page
  53. [61]Geller LT, Barzily-Rokni M, Danino T, Jonas OH, Shental N, Nejman D, et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 357: 1156– 1160, 2017. doi: 10.1126/science.aah5043. 28912244 PMC5727343 · DOI · Paper page
  54. [62]Garcia PE, Scales MK, Allen BL, Di Pasca Magliano M. Pancreatic fibroblast heterogeneity: from development to cancer. Cells 9: 2464, 2020. doi: 10.3390/cells9112464. 33198201 PMC7698149 · DOI
  55. [63]Helms E, Onate MK, Sherman MH. Fibroblast heterogeneity in the pancreatic tumor microenvironment. Cancer Discov 10: 648– 656, 2020. doi: 10.1158/2159-8290.CD-19-1353. 32014869 PMC8261791 · DOI
  56. [65]Elyada E, Bolisetty M, Laise P, Flynn WF, Courtois ET, Burkhart RA, Teinor JA, Belleau P, Biffi G, Lucito MS, Sivajothi S, Armstrong TD, Engle DD, Yu KH, Hao Y, Wolfgang CL, Park Y, Preall J, Jaffee EM, Califano A, Robson P, Tuveson DA. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov 9: 1102– 1123, 2019. doi: 10.1158/2159-8290.CD-19-0094. 31197017 PMC6727976 · DOI · Paper page
  57. [66]Wu J, Liang C, Chen M, Su W. Association between tumor-stroma ratio and prognosis in solid tumor patients: a systematic review and meta-analysis. Oncotarget 7: 68954– 68965, 2016. doi: 10.18632/oncotarget.12135. 27661111 PMC5356603 · DOI
  58. [67]Whatcott CJ, Diep CH, Jiang P, Watanabe A, LoBello J, Sima C, Hostetter G, Shepard HM, Von Hoff DD, Han H. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin Cancer Res 21: 3561– 3568, 2015. doi: 10.1158/1078-0432.CCR-14-1051. 25695692 PMC4526394 · DOI
  59. [68]Mahajan UM, Langhoff E, Goni E, Costello E, Greenhalf W, Halloran C, Ormanns S, Kruger S, Boeck S, Ribback S, Beyer G, Dombroswki F, Weiss F-U, Neoptolemos JP, Werner J, D'Haese JG, Bazhin A, Peterhansl J, Pichlmeier S, Büchler MW, Kleeff J, Ganeh P, Sendler M, Palmer DH, Kohlmann T, Rad R, Regel I, Lerch MM, Mayerle J. Immune cell and stromal signature associated with progression-free survival of patients with resected pancreatic ductal adenocarcinoma. Gastroenterology 155: 1625– 1639.e2, 2018. doi: 10.1053/j.gastro.2018.08.009. 30092175 · DOI
  60. [71]Gu Z, Du Y, Zhao X, Wang C. Tumor microenvironment and metabolic remodeling in gemcitabine-based chemoresistance of pancreatic cancer. Cancer Lett 521: 98– 108, 2021. doi: 10.1016/j.canlet.2021.08.029. 34461181 · DOI
  61. [72]Zhu Y, Herndon JM, Sojka DK, Kim K-W, Knolhoff BL, Zuo C, Cullinan DR, Luo J, Bearden AR, Lavine KJ, Yokoyama WM, Hawkins WG, Fields RC, Randolph GJ, DeNardo DG. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47: 323– 338.e6, 2017. doi: 10.1016/j.immuni.2017.07.014. 28813661 PMC5578409 · DOI
  62. [73]Liou G-Y, Döppler H, Necela B, Edenfield B, Zhang L, Dawson DW, Storz P. Mutant KRAS-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. Cancer Discov 5: 52– 63, 2015. doi: 10.1158/2159-8290.CD-14-0474. 25361845 PMC4293204 · DOI
  63. [74]Poh AR, Ernst M. Tumor-associated macrophages in pancreatic ductal adenocarcinoma: therapeutic opportunities and clinical challenges. Cancers (Basel) 13: 2860, 2021. doi: 10.3390/cancers13122860. 34201127 PMC8226457 · DOI · Paper page
  64. [75]Zhang Y, Yan W, Mathew E, Kane KT, Brannon A, Adoumie M, Vinta A, Crawford HC, Di Pasca Magliano M. Epithelial-myeloid cell crosstalk regulates acinar cell plasticity and pancreatic remodeling in mice. eLife 6: e27388, 2017. doi: 10.7554/eLife.27388. 28980940 PMC5690281 · DOI
  65. [78]Pushalkar S, Hundeyin M, Daley D, Zambirinis CP, Kurz E, Mishra A, Mohan N, Aykut B, Usyk M, Torres LE, Werba G, Zhang K, Guo Y, Li Q, Akkad N, Lall S, Wadowski B, Gutierrez J, Kochen Rossi JA, Herzog JW, Diskin B, Torres-Hernandez A, Leinwand J, Wang W, Taunk PS, Savadkar S, Janal M, Saxena A, Li X, Cohen D, Balfour Saltor R, Saxena D, Miller G. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov 8: 403– 416, 2018. doi: 10.1158/2159-8290.CD-17-1134. 29567829 PMC6225783 · DOI · Paper page
  66. [79]Gasparini G, Pellegatta M, Crippa S, Lena MS, Belfiori G, Doglioni C, Taveggia C, Falconi M. Nerves and pancreatic cancer: new insights into a dangerous relationship. Cancers (Basel) 11: 893, 2019. doi: 10.3390/cancers11070893. 31248001 PMC6678884 · DOI
  67. [80]Renz BW, Takahashi R, Tanaka T, Macchini M, Hayakawa Y, Dantes Z, Maurer HC, Chen X, Jiang Z, Westphalen CB, Ilmer M, Valenti G, Mohanta SK, Habenicht AJR, Middelhoff M, Chu T, Nagar K, Tailor Y, Casadei R, Di Marco M, Kleespies A, Friedman RA, Remotti H, Reichert M, Worthley DL, Neumann J, Werner J, Iuga AC, Olive KP, Wang TC. β2 Adrenergic-neurotrophin feedforward loop promotes pancreatic cancer. Cancer Cell 33: 75– 90.e7, 2018. doi: 10.1016/j.ccell.2017.11.007. 29249692 PMC5760435 · DOI · Paper page
  68. [81]Saloman JL, Albers KM, Li D, Hartman DJ, Crawford HC, Muha EA, Rhim AD, Davis BM. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. Proc Natl Acad Sci USA 113: 3078– 3083, 2016. doi: 10.1073/pnas.1512603113. 26929329 PMC4801275 · DOI
  69. [82]Saloman JL, Singhi AD, Hartman DJ, Normolle DP, Albers KM, Davis BM. Systemic depletion of nerve growth factor inhibits disease progression in a genetically engineered model of pancreatic ductal adenocarcinoma. Pancreas 47: 856– 863, 2018. doi: 10.1097/MPA.0000000000001090. 29975347 PMC6044729 · DOI
  70. [83]Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials. Lancet Oncol 21: 271– 282, 2020. doi: 10.1016/S1470-2045(19)30691-6. 31838007 PMC7461630 · DOI · Paper page
  71. [84]Hong DS, DuBois SG, Kummar S, Farago AF, Albert CM, Rohrberg KS, van Tilburg CM, Nagasubramanian R, Berlin JD, Federman N, Mascarenhas L, Geoerger B, Dowlati A, Pappo AS, Bielack S, Doz F, McDermott R, Patel JD, Schilder RJ, Tahara M, Pfister SM, Witt O, Ladanyi M, Rudzinski ER, Nanda S, Childs BH, Laetsch TW, Hyman DM, Drilon A. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol 21: 531– 540, 2020. doi: 10.1016/S1470-2045(19)30856-3. 32105622 PMC7497841 · DOI · Paper page
  72. [85]Cao Y. Adipocyte and lipid metabolism in cancer drug resistance. J Clin Invest 129: 3006– 3017, 2019. doi: 10.1172/JCI127201. 31264969 PMC6668696 · DOI
  73. [86]Elaskalani O, Falasca M, Moran N, Berndt MC, Metharom P. The role of platelet-derived ADP and ATP in promoting pancreatic cancer cell survival and gemcitabine resistance. Cancers (Basel) 9: 142, 2017. doi: 10.3390/cancers9100142. 29064388 PMC5664081 · DOI
  74. [87]Veronese FM, Mero A. The impact of PEGylation on biological therapies. BioDrugs 22: 315– 329, 2008. doi: 10.2165/00063030-200822050-00004. 18778113 · DOI
  75. [88]Vandana M, Sahoo SK. Long circulation and cytotoxicity of PEGylated gemcitabine and its potential for the treatment of pancreatic cancer. Biomaterials 31: 9340– 9356, 2010. doi: 10.1016/j.biomaterials.2010.08.010. 20851464 · DOI
  76. [89]Réjiba S, Reddy LH, Bigand C, Parmentier C, Couvreur P, Hajri A. Squalenoyl gemcitabine nanomedicine overcomes the low efficacy of gemcitabine therapy in pancreatic cancer. Nanomedicine 7: 841– 849, 2011. doi: 10.1016/j.nano.2011.02.012. 21419876 · DOI
  77. [90]Stuurman FE, Voest EE, Awada A, Witteveen PO, Bergeland T, Hals P-A, Rasch W, Schellens JHM, Hendlisz A. Phase I study of oral CP-4126, a gemcitabine derivative, in patients with advanced solid tumors. Invest New Drugs 31: 959– 966, 2013. doi: 10.1007/s10637-013-9925-z. 23345000 · DOI
  78. [91]Wu W, Sigmond J, Peters GJ, Borch RF. Synthesis and biological activity of a gemcitabine phosphoramidate prodrug. J Med Chem 50: 3743– 3746, 2007. doi: 10.1021/jm070269u. 17602464 PMC2518329 · DOI
  79. [92]Blagden SP, Rizzuto I, Suppiah P, O'Shea D, Patel M, Spiers L, Sukumaran A, Bharwani N, Rockall A, Gabra H, El-Bahrawy M, Wasan H, Leonard R, Habib N, Ghazaly E. Anti-tumour activity of a first-in-class agent NUC-1031 in patients with advanced cancer: results of a phase I study. Br J Cancer 119: 815– 822, 2018. doi: 10.1038/s41416-018-0244-1. 30206366 PMC6189138 · DOI
  80. [93]Bailey JM, Swanson BJ, Hamada T, Eggers JP, Singh PK, Caffery T, Ouellette MM, Hollingsworth MA. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res 14: 5995– 6004, 2008. doi: 10.1158/1078-0432.CCR-08-0291. 18829478 PMC2782957 · DOI
  81. [94]Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324: 1457– 1461, 2009. doi: 10.1126/science.1171362. 19460966 PMC2998180 · DOI · Paper page
  82. [95]Jesus-Acosta A. D, Sugar EA, O'Dwyer PJ, Ramanathan RK, Hoff DD. V, Rasheed Z, Zheng L, Begum A, Anders R, Maitra A, McAllister F, Rajeshkumar NV, Yabuuchi S, Wilde R. D, Batukbhai B, Sahin I, Laheru DA. Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma. Br J Cancer 122: 498– 505, 2020. doi: 10.1038/s41416-019-0683-3. 31857726 PMC7029016 · DOI
  83. [96]Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon JM, Meyer MA, Nywening TM, Hawkins WG, Shapiro IM, Weaver DT, Pachter JA, Wang-Gillam A, DeNardo DG. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med 22: 851– 860, 2016. doi: 10.1038/nm.4123. 27376576 PMC4935930 · DOI · Paper page
  84. [97]Le Large TYS, Bijlsma MF, El Hassouni B, Mantini G, Lagerweij T, Henneman AA, Funel N, Kok B, Pham TV, de Haas R, Morelli L, Knol JC, Piersma SR, Kazemier G, van Laarhoven HWM, Giovannetti E, Jimenez CR. Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma. J Exp Clin Cancer Res 40: 91, 2021. doi: 10.1186/s13046-021-01892-z. 33750427 PMC7941981 · DOI
  85. [98]Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21: 418– 429, 2012. doi: 10.1016/j.ccr.2012.01.007. 22439937 PMC3371414 · DOI · Paper page
  86. [99]Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, Feig C, Nakagawa T, Caldwell ME, Zecchini HI, Lolkema MP, Jiang P, Kultti A, Thompson CB, Maneval DC, Jodrell DI, Frost GI, Shepard HM, Skepper JN, Tuveson DA. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62: 112– 120, 2013. doi: 10.1136/gutjnl-2012-302529. 22466618 PMC3551211 · DOI · Paper page
  87. [100]van Cutsem E, Tempero MA, Sigal D, Oh D-Y, Fazio N, Macarulla T, Hitre E, Hammel P, Hendifar AE, Bates SE, Li C-P, Hingorani SR, La Fouchardiere C. D, Kasi A, Heinemann V, Maraveyas A, Bahary N, Layos L, Sahai V, Zheng L, Lacy J, Park JO, Portales F, Oberstein P, Wu W, Chondros D, Bullock AJ; HALO 109-301 Investigators. Randomized phase III trial of pegvorhyaluronidase alfa with nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic pancreatic adenocarcinoma. J Clin Oncol 38: 3185– 3194, 2020. doi: 10.1200/JCO.20.00590. 32706635 PMC7499614 · DOI · Paper page
  88. [102]van Cutsem E, Lenz H-J, Furuse J, Tabernero J, Heinemann V, Ioka T, Bazin I, Ueno M, Csõszi T, Wasan H, Melichar B, Karasek P, Macarulla TM, Guillen C, Kalinka-Warzocha E, Horvath Z, Prenen H, Schlichting M, Ibrahim A, Bendell JC. MAESTRO: A randomized, double-blind phase III study of evofosfamide (Evo) in combination with gemcitabine (Gem) in previously untreated patients (pts) with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC). J Clin Oncol 34: 4007, 2016. doi: 10.1200/JCO.2016.34.15_suppl.4007. · DOI
  89. [103]Cassier PA, Garin G, Eberst L, Delord J-P, Chabaud S, Terret C, Montane L, Bidaux A-S, Laurent S, Jaubert L, Ferlay C, Bernardin M, Tabone-Eglinger S, Gilles-Afchain L, Menetrier-Caux C, Caux C, Treilleux I, Pérol D, Gomez-Roca CA. MEDIPLEX: A phase 1 study of durvalumab (D) combined with pexidartinib (P) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). J Clin Oncol 37: 2579, 2019. doi: 10.1200/JCO.2019.37.15_suppl.2579. · DOI
  90. [104]Céspedes MV, Guillén MJ, López-Casas PP, Sarno F, Gallardo A, Álamo P, Cuevas C, Hidalgo M, Galmarini CM, Allavena P, Avilés P, Mangues R. Lurbinectedin induces depletion of tumor-associated macrophages, an essential component of its in vivo synergism with gemcitabine, in pancreatic adenocarcinoma mouse models. Dis Model Mech 9: 1461– 1471, 2016. doi: 10.1242/dmm.026369. 27780828 PMC5200894 · DOI
  91. [105]Sullivan MR, Danai LV, Lewis CA, Chan SH, Gui DY, Kunchok T, Dennstedt EA, Vander Heiden MG, Muir A. Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability. eLife 8: e44235, 2019. doi: 10.7554/eLife.44235. 30990168 PMC6510537 · DOI · Paper page
  92. [107]Cheung EC, DeNicola GM, Nixon C, Blyth K, Labuschagne CF, Tuveson DA, Vousden KH. Dynamic ROS control by TIGAR regulates the initiation and progression of pancreatic cancer. Cancer Cell 37: 168– 182.e4, 2020. doi: 10.1016/j.ccell.2019.12.012. 31983610 PMC7008247 · DOI
  93. [109]Patki M, Saraswat A, Bhutkar S, Dukhande V, Patel K. In vitro assessment of a synergistic combination of gemcitabine and zebularine in pancreatic cancer cells. Exp Cell Res 405: 112660, 2021. doi: 10.1016/j.yexcr.2021.112660. 34048785 · DOI
  94. [110]Sohal D, Krishnamurthi S, Tohme R, Gu X, Lindner D, Landowski TH, Pink J, Radivoyevitch T, Fada S, Lee Z, Shepard D, Khorana A, Saunthararajah Y. A pilot clinical trial of the cytidine deaminase inhibitor tetrahydrouridine combined with decitabine to target DNMT1 in advanced, chemorefractory pancreatic cancer. Am J Cancer Res 10: 3047– 3060, 2020. 33042633 PMC7539776
  95. [111]Jiang W, Hu J-W, He X-R, Jin W-L, He X-Y. Statins: a repurposed drug to fight cancer. J Exp Clin Cancer Res 40: 241, 2021. doi: 10.1186/s13046-021-02041-2. 34303383 PMC8306262 · DOI · Paper page
  96. [112]McGregor GH, Campbell AD, Fey SK, Tumanov S, Sumpton D, Blanco GR, Mackay G, Nixon C, Vazquez A, Sansom OJ, Kamphorst JJ. Targeting the metabolic response to statin-mediated oxidative stress produces a synergistic antitumor response. Cancer Res 80: 175– 188, 2020. doi: 10.1158/0008-5472.CAN-19-0644. 31562248 · DOI
  97. [113]Hong JY, Nam EM, Lee J, Park JO, Lee S-C, Song S-Y, Choi SH, Heo JS, Park SH, Lim HY, Kang WK, Park YS. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol 73: 125– 130, 2014. doi: 10.1007/s00280-013-2328-1. 24162380 · DOI
  98. [114]Eibl G, Rozengurt E. Metformin: review of epidemiology and mechanisms of action in pancreatic cancer. Cancer Metastasis Rev 40: 865– 878, 2021. doi: 10.1007/s10555-021-09977-z. 34142285 PMC8556217 · DOI
  99. [117]Mukhopadhyay S, Goswami D, Adiseshaiah PP, Burgan W, Yi M, Guerin TM, Kozlov SV, Nissley DV, McCormick F. Undermining glutaminolysis bolsters chemotherapy while NRF2 promotes chemoresistance in KRAS-driven pancreatic cancers. Cancer Res 80: 1630– 1643, 2020. doi: 10.1158/0008-5472.CAN-19-1363. 31911550 PMC7185043 · DOI · Paper page

Cited by

Sorted by citations

Authors
Beutel, A. K., & Halbrook, C. J.
Affiliations
University of California, Irvine (US)
Corresponding author
Halbrook, Christopher J.
ORCID
Halbrook, Christopher J.
Venue
American Journal of Physiology-Cell Physiology
Publisher
American Physiological Society
Published
2023-02-01
Volume
324
Issue
2
Pages
C540-C552
ISSN
  • 0363-6143 (ISSN-L)
  • 1522-1563
DOI
10.1152/ajpcell.00331.2022
PMC
PMC9925166
OpenAlex
W4312195030
Cited by
150
References
17
Citations by year
2026: 32 · 2025: 67 · 2024: 40 · 2023: 11
FWCI
3.60
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • American Journal of Physiology-Cell Physiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • University of California, Irvine (Anti-Cancer Challenge Pilot Award)
  • Deutsche Krebshilfe (Mildred-Scheel-Postdoktorandenstipendium)
  • HHS | NIH | National Cancer Institute (R00CA241357, P30CA062203)
  • National Pancreas Foundation
  • Sky Foundation
  • V Foundation for Cancer Research (V2021-026)
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
gemcitabine, pancreatic ductal adenocarcinoma, gemcitabine resistance, chemoresistance mechanisms, pyrimidine antimetabolites
MeSH terms
Gemcitabine, Deoxycytidine, Humans, Pancreatic Neoplasms, Drug Resistance, Neoplasm, Carcinoma, Pancreatic Ductal, Cell Line, Tumor

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