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Review

Regulation and function of autophagy in pancreatic cancer

, , , , ORCID Icon & ORCID Icon
Pages 3275-3296 | Received 09 Jul 2020, Accepted 02 Nov 2020, Published online: 20 Nov 2020

References

  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.
  • Kleeff J, Korc M, Apte M, et al. Pancreatic cancer. Nat Rev Dis Primers. 2016;2:16022.
  • Hingorani SR, Petricoin EF, Maitra A, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4:437–450.
  • Neoptolemos JP, Kleeff J, Michl P, et al. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol. 2018;15:333–348.
  • Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–1825.
  • Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–1703.
  • Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science. 2000;290:1717–1721.
  • Levine B, Kroemer G. Biological functions of autophagy genes: a disease perspective. Cell. 2019;176:11–42.
  • Kroemer G, Marino G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40:280–293.
  • Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. 2017;17:528–542.
  • Pohl C, Dikic I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science. 2019;366:818–822.
  • Tsukada M, Ohsumi Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 1993;333:169–174.
  • Thumm M, Egner R, Koch B, et al. Isolation of autophagocytosis mutants of Saccharomyces cerevisiae. FEBS Lett. 1994;349:275–280.
  • Harding TM, Morano KA, Scott SV, et al. Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway. J Cell Biol. 1995;131:591–602.
  • Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol. 2018;19:349–364.
  • Xie Y, Kang R, Sun X, et al. Posttranslational modification of autophagy-related proteins in macroautophagy. Autophagy. 2015;11:28–45.
  • Paquette M, El-Houjeiri L, Pause A. mTOR pathways in cancer and autophagy. Cancers (Basel). 2018;10:18 1 doi:10.3390/cancers10010018
  • Kabeya Y, Mizushima N, Ueno T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. Embo J. 2000;19:5720–5728.
  • Kabeya Y, Mizushima N, Yamamoto A, et al. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J Cell Sci. 2004;117:2805–2812.
  • Pasquier B. Autophagy inhibitors. Cell Mol Life Sci. 2016;73:985–1001.
  • Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140:313–326.
  • Reggiori F, Komatsu M, Finley K, et al. Autophagy: more than a nonselective pathway. Int J Cell Biol. 2012;2012:219625.
  • Kirkin V, McEwan DG, Novak I, et al. A role for ubiquitin in selective autophagy. Mol Cell. 2009;34:259–269.
  • Johansen T, Lamark T. Selective autophagy: ATG8 family proteins, LIR motifs and cargo receptors. J Mol Biol. 2020;432:80–103.
  • Ko YH, Cho YS, Won HS, et al. Prognostic significance of autophagy-related protein expression in resected pancreatic ductal adenocarcinoma. Pancreas. 2013;42:829–835.
  • Perera RM, Stoykova S, Nicolay BN, et al. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature. 2015;524:361–365.
  • Settembre C, Di Malta C, Polito VA, et al. TFEB links autophagy to lysosomal biogenesis. Science. 2011;332:1429–1433.
  • Wong PM, Feng Y, Wang J, et al. Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A. Nat Commun. 2015;6:8048.
  • Resau JH, Cottrell JR, Hudson EA, et al. Studies on the mechanisms of altered exocrine acinar cell differentiation and ductal metaplasia following nitrosamine exposure using hamster pancreatic explant organ culture. Carcinogenesis. 1985;6:29–35.
  • Flaks B, Moore MA, Flaks A. Ultrastructural analysis of pancreatic carcinogenesis. IV. Pseudoductular transformation of acini in the hamster pancreas during N-nitroso-bis(2-hydroxypropyl)amine carcinogenesis. Carcinogenesis. 1981;2:1241–1253.
  • Rez G, Toth S, Palfia Z. Cellular autophagic capacity is highly increased in azaserine-induced premalignant atypical acinar nodule cells. Carcinogenesis. 1999;20:1893–1898.
  • Park CH, Lee IS, Grippo P, et al. Akt kinase mediates the prosurvival effect of smoking compounds in pancreatic ductal cells. Pancreas. 2013;42:655–662.
  • Tsang YH, Wang Y, Kong K, et al. Differential expression of MAGEA6 toggles autophagy to promote pancreatic cancer progression. Elife. 2020;9:e48963
  • Antonucci L, Fagman JB, Kim JY, et al. Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress. Proc Natl Acad Sci U S A. 2015;112:E6166–74.
  • Zhou X, Xie L, Xia L, et al. RIP3 attenuates the pancreatic damage induced by deletion of ATG7. Cell Death Dis. 2017;8:e2918.
  • Mathew R, Khor S, Hackett SR, et al. Functional role of autophagy-mediated proteome remodeling in cell survival signaling and innate immunity. Mol Cell. 2014;55:916–930.
  • Yang S, Imamura Y, Jenkins RW, et al. Autophagy inhibition dysregulates TBK1 signaling and promotes pancreatic inflammation. Cancer Immunol Res. 2016;4:520–530.
  • Tang D, Kang R, Livesey KM, et al. Endogenous HMGB1 regulates autophagy. J Cell Biol. 2010;190:881–892.
  • Kang R, Xie Y, Zhang Q, et al. Intracellular HMGB1 as a novel tumor suppressor of pancreatic cancer. Cell Res. 2017;27:916–932.
  • Molejon MI, Ropolo A, Re AL, et al. The VMP1-Beclin 1 interaction regulates autophagy induction. Sci Rep. 2013;3:1055.
  • Loncle C, Molejon MI, Lac S, et al. The pancreatitis-associated protein VMP1, a key regulator of inducible autophagy, promotes Kras(G12D)-mediated pancreatic cancer initiation. Cell Death Dis. 2016;7:e2295.
  • Maes H, Kuchnio A, Peric A, et al. Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell. 2014;26:190–206.
  • Todoric J, Antonucci L, Di Caro G, et al. Stress-activated NRF2-MDM2 cascade controls neoplastic progression in pancreas. Cancer Cell. 2017;32:824–39 e8.
  • Komatsu M, Kurokawa H, Waguri S, et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol. 2010;12:213–223.
  • Ichimura Y, Waguri S, Sou YS, et al. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell. 2013;51:618–631.
  • Nigro JM, Baker SJ, Preisinger AC, et al. Mutations in the p53 gene occur in diverse human tumour types. Nature. 1989;342:705–708.
  • Yang A, Rajeshkumar NV, Wang X, et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 2014;4:905–913.
  • Rosenfeldt MT, O’Prey J, Morton JP, et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature. 2013;504:296–300.
  • Amaravadi R, Debnath J. Mouse models address key concerns regarding autophagy inhibition in cancer therapy. Cancer Discov. 2014;4:873–875.
  • Rosenfeldt MT, O’Prey J, Flossbach L, et al. PTEN deficiency permits the formation of pancreatic cancer in the absence of autophagy. Cell Death Differ. 2017;24:1303–1304.
  • Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011;12:9–14.
  • Li C, Zhang Y, Cheng X, et al. PINK1 and PARK2 suppress pancreatic tumorigenesis through control of mitochondrial iron-mediated immunometabolism. Dev Cell. 2018;46:441–55 e8.
  • Humpton TJ, Alagesan B, DeNicola GM, et al. Oncogenic KRAS induces NIX-mediated mitophagy to promote pancreatic cancer. Cancer Discov. 2019;9:1268–1287.
  • Viale A, Pettazzoni P, Lyssiotis CA, et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature. 2014;514:628–632.
  • Alcala S, Sancho P, Martinelli P, et al. ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity. Nat Commun. 2020;11:2682.
  • Yang S, Wang X, Contino G, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011;25:717–729.
  • Hwang RF, Moore T, Arumugam T, et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 2008;68:918–926.
  • Endo S, Nakata K, Ohuchida K, et al. Autophagy is required for activation of pancreatic stellate cells, associated with pancreatic cancer progression and promotes growth of pancreatic tumors in mice. Gastroenterology. 2017;152:1492–506 e24.
  • Okada S, Okusaka T, Ishii H, et al. Elevated serum interleukin-6 levels in patients with pancreatic cancer. Jpn J Clin Oncol. 1998;28:12–15.
  • Lesina M, Kurkowski MU, Ludes K, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell. 2011;19:456–469.
  • Sousa CM, Biancur DE, Wang X, et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature. 2016;536:479–483.
  • Sun L, Hu L, Cogdell D, et al. MIR506 induces autophagy-related cell death in pancreatic cancer cells by targeting the STAT3 pathway. Autophagy. 2017;13:703–714.
  • Chen H, Zhang Z, Lu Y, et al. Downregulation of ULK1 by microRNA-372 inhibits the survival of human pancreatic adenocarcinoma cells. Cancer Sci. 2017;108:1811–1819.
  • Huang F, Chen W, Peng J, et al. LncRNA PVT1 triggers Cyto-protective autophagy and promotes pancreatic ductal adenocarcinoma development via the miR-20a-5p/ULK1 Axis. Mol Cancer. 2018;17:98.
  • New M, Van Acker T, Sakamaki JI, et al. MDH1 and MPP7 regulate autophagy in pancreatic ductal adenocarcinoma. Cancer Res. 2019;79:1884–1898.
  • Lee DE, Yoo JE, Kim J, et al. NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter. Cell Death Dis. 2020;11:38.
  • Sparvero LJ, Asafu-Adjei D, Kang R, et al. RAGE (receptor for advanced glycation endproducts), RAGE ligands, and their role in cancer and inflammation. J Transl Med. 2009;7:17.
  • Kang R, Tang D, Schapiro NE, et al. The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival. Cell Death Differ. 2010;17:666–676.
  • Kang R, Loux T, Tang D, et al. The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia. Proc Natl Acad Sci U S A. 2012;109:7031–7036.
  • Collisson EA, Trejo CL, Silva JM, et al. A central role for RAF–>MEK–>ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov. 2012;2:685–693.
  • Kinsey CG, Camolotto SA, Boespflug AM, et al. Protective autophagy elicited by RAF–>MEK–>ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med. 2019;25:620–627.
  • Boone BA, Orlichenko L, Schapiro NE, et al. The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer. Cancer Gene Ther. 2015;22:326–334.
  • Xie CM, Tan M, Lin XT, et al. The FBXW7-SHOC2-raptor axis controls the cross-talks between the RAS-ERK and mTORC1 signaling pathways. Cell Rep. 2019;26:3037–50 e4.
  • Hwang M, Jun DW, Kang EH, et al. EI24, as a component of autophagy, is involved in pancreatic cell proliferation. Front Oncol. 2019;9:652.
  • Li L, Chen H, Gao Y, et al. Long noncoding RNA MALAT1 promotes aggressive pancreatic cancer proliferation and metastasis via the stimulation of autophagy. Mol Cancer Ther. 2016;15:2232–2243.
  • Song B, Bian Q, Zhang YJ, et al. Downregulation of ASPP2 in pancreatic cancer cells contributes to increased resistance to gemcitabine through autophagy activation. Mol Cancer. 2015;14:177.
  • Das B, Senapati S. Functional and mechanistic studies reveal MAGEA3 as a pro-survival factor in pancreatic cancer cells. J Exp Clin Cancer Res. 2019;38:294.
  • Gong C, Bauvy C, Tonelli G, et al. Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stem-like/progenitor cells. Oncogene. 2013;32:2261–72,72e 1–11.
  • Yang MC, Wang HC, Hou YC, et al. Blockade of autophagy reduces pancreatic cancer stem cell activity and potentiates the tumoricidal effect of gemcitabine. Mol Cancer. 2015;14:179.
  • Gorgulu K, Diakopoulos KN, Ai J, et al. Levels of the autophagy-related 5 protein affect progression and metastasis of pancreatic tumors in mice. Gastroenterology. 2019;156:203–17 e20.
  • Akar U, Ozpolat B, Mehta K, et al. Tissue transglutaminase inhibits autophagy in pancreatic cancer cells. Mol Cancer Res. 2007;5:241–249.
  • Ozpolat B, Akar U, Mehta K, et al. PKC delta and tissue transglutaminase are novel inhibitors of autophagy in pancreatic cancer cells. Autophagy. 2007;3:480–483.
  • He R, Wang M, Zhao C, et al. TFEB-driven autophagy potentiates TGF-beta induced migration in pancreatic cancer cells. J Exp Clin Cancer Res. 2019;38:340.
  • Liang C, Xu J, Meng Q, et al. TGFB1-induced autophagy affects the pattern of pancreatic cancer progression in distinct ways depending on SMAD4 status. Autophagy. 2020;16:486–500.
  • Martin TD, Chen XW, Kaplan RE, et al. Ral and Rheb GTPase activating proteins integrate mTOR and GTPase signaling in aging, autophagy, and tumor cell invasion. Mol Cell. 2014;53:209–220.
  • Chen H, Li L, Hu J, et al. UBL4A inhibits autophagy-mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting LAMP1. J Exp Clin Cancer Res. 2019;38:297.
  • Chu L, Hu Y, Jiang YH, et al. Effects of RNA binding protein QKI on pancreatic cancer ductal epithelial cells and surrounding activation fibroblasts. J Cell Biochem. 2019;120:11551–11561.
  • Yan Z, Ohuchida K, Fei S, et al. Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer-stromal interaction and metastasis. J Exp Clin Cancer Res. 2019;38:221.
  • Wang Y, Xiong H, Liu D, et al. Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells. Autophagy. 2019;15:886–899.
  • Alexander J, Valvezan BDM. Molecular logic of mTORC1 signalling as a metabolic rheostat. Nat Metab. 2019;1:321–333.
  • Di Malta C, Siciliano D, Calcagni A, et al. Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth. Science. 2017;356:1188–1192.
  • Hamidi T, Cano CE, Grasso D, et al. Nupr1-aurora kinase A pathway provides protection against metabolic stress-mediated autophagic-associated cell death. Clin Cancer Res. 2012;18:5234–5246.
  • Alexander A, Cai SL, Kim J, et al. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci U S A. 2010;107:4153–4158.
  • Zhang L, Li J, Ma J, et al. The relevance of Nrf2 pathway and autophagy in pancreatic cancer cells upon stimulation of reactive oxygen species. Oxid Med Cell Longev. 2016;2016:3897250.
  • Kang R, Tang D, Schapiro NE, et al. The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics. Oncogene. 2014;33:567–577.
  • Singh AP, Moniaux N, Chauhan SC, et al. Inhibition of MUC4 expression suppresses pancreatic tumor cell growth and metastasis. Cancer Res. 2004;64:622–630.
  • Joshi S, Kumar S, Ponnusamy MP, et al. Hypoxia-induced oxidative stress promotes MUC4 degradation via autophagy to enhance pancreatic cancer cells survival. Oncogene. 2016;35:5882–5892.
  • Yu Z, Zhou R, Zhao Y, et al. Blockage of SLC31A1-dependent copper absorption increases pancreatic cancer cell autophagy to resist cell death. Cell Prolif. 2019;52:e12568.
  • Rademaker G, Hennequiere V, Brohee L, et al. Myoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness. Oncogene. 2018;37:4398–4412.
  • Bryant KL, Mancias JD, Kimmelman AC, et al. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci. 2014;39:91–100.
  • Gu DN, Jiang MJ, Mei Z, et al. microRNA-7 impairs autophagy-derived pools of glucose to suppress pancreatic cancer progression. Cancer Lett. 2017;400:69–78.
  • Meng Q, Xu J, Liang C, et al. GPx1 is involved in the induction of protective autophagy in pancreatic cancer cells in response to glucose deprivation. Cell Death Dis. 2018;9:1187.
  • Li X, Deng S, Liu M, et al. The responsively decreased PKM2 facilitates the survival of pancreatic cancer cells in hypoglucose. Cell Death Dis. 2018;9:133.
  • Shiratori R, Furuichi K, Yamaguchi M, et al. Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner. Sci Rep. 2019;9:18699.
  • Maertin S, Elperin JM, Lotshaw E, et al. Roles of autophagy and metabolism in pancreatic cancer cell adaptation to environmental challenges. Am J Physiol Gastrointest Liver Physiol. 2017;313:G524–G36.
  • Zhou C, Qian W, Li J, et al. High glucose microenvironment accelerates tumor growth via SREBP1-autophagy axis in pancreatic cancer. J Exp Clin Cancer Res. 2019;38:302.
  • Kinsey C, Balakrishnan V, O’Dell MR, et al. Plac8 links oncogenic mutations to regulation of autophagy and is critical to pancreatic cancer progression. Cell Rep. 2014;7:1143–1155.
  • Bryant KL, Stalnecker CA, Zeitouni D, et al. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat Med. 2019;25:628–640.
  • Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci. 2010;35:427–433.
  • Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 2009;23:537–548.
  • Eng CH, Abraham RT. Glutaminolysis yields a metabolic by-product that stimulates autophagy. Autophagy. 2010;6:968–970.
  • Son J, Lyssiotis CA, Ying H, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013;496:101–105.
  • Duran RV, Oppliger W, Robitaille AM, et al. Glutaminolysis activates Rag-mTORC1 signaling. Mol Cell. 2012;47:349–358.
  • Seo JW, Choi J, Lee SY, et al. Autophagy is required for PDAC glutamine metabolism. Sci Rep. 2016;6:37594.
  • Commisso C, Davidson SM, Soydaner-Azeloglu RG, et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature. 2013;497:633–637.
  • Jeong SM, Hwang S, Park K, et al. Enhanced mitochondrial glutamine anaplerosis suppresses pancreatic cancer growth through autophagy inhibition. Sci Rep. 2016;6:30767.
  • Wyant GA, Abu-Remaileh M, Wolfson RL, et al. mTORC1 activator SLC38A9 is required to efflux essential amino acids from lysosomes and use protein as a nutrient. Cell. 2017;171:642–54 e12.
  • Tang D, Kang R, Berghe TV, et al. The molecular machinery of regulated cell death. Cell Res. 2019;29:347–364.
  • Codogno P, Meijer AJ. Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ. 2005;12(Suppl 2):1509–1518.
  • Galluzzi L, Vitale I, Aaronson SA, et al. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. 2018;25:486–541.
  • Kang R, Tang D, Livesey KM, et al. The receptor for advanced glycation end-products (RAGE) protects pancreatic tumor cells against oxidative injury. Antioxid Redox Signal. 2011;15:2175–2184.
  • Kang R, Hou W, Zhang Q, et al. RAGE is essential for oncogenic KRAS-mediated hypoxic signaling in pancreatic cancer. Cell Death Dis. 2014;5:e1480.
  • Guzman EA, Pitts TP, Diaz MC, et al. The marine natural product Scalarin inhibits the receptor for advanced glycation end products (RAGE) and autophagy in the PANC-1 and MIA PaCa-2 pancreatic cancer cell lines. Invest New Drugs. 2019;37:262–270.
  • Donadelli M, Dando I, Fiorini C, et al. UCP2, a mitochondrial protein regulated at multiple levels. Cell Mol Life Sci. 2014;71:1171–1190.
  • Dando I, Pacchiana R, Pozza ED, et al. UCP2 inhibition induces ROS/Akt/mTOR axis: role of GAPDH nuclear translocation in genipin/everolimus anticancer synergism. Free Radic Biol Med. 2017;113:176–189.
  • Perez-Galan P, Roue G, Villamor N, et al. The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood. 2006;107:257–264.
  • Li X, Liang M, Jiang J, et al. Combined inhibition of autophagy and Nrf2 signaling augments bortezomib-induced apoptosis by increasing ROS production and ER stress in pancreatic cancer cells. Int J Biol Sci. 2018;14:1291–1305.
  • Liang JX, Ning Z, Gao W, et al. Ubiquitinspecific protease 22induced autophagy is correlated with poor prognosis of pancreatic cancer. Oncol Rep. 2014;32:2726–2734.
  • Ma J, Weng L, Jia Y, et al. PTBP3 promotes malignancy and hypoxia-induced chemoresistance in pancreatic cancer cells by ATG12 up-regulation. J Cell Mol Med. 2020;24:2917–2930.
  • Zhang XY, Varthi M, Sykes SM, et al. The putative cancer stem cell marker USP22 is a subunit of the human SAGA complex required for activated transcription and cell-cycle progression. Mol Cell. 2008;29:102–111.
  • Wang D, Zhu H, Zhu Y, et al. CD133(+)/CD44(+)/Oct4(+)/Nestin(+) stem-like cells isolated from Panc-1 cell line may contribute to multi-resistance and metastasis of pancreatic cancer. Acta Histochem. 2013;115:349–356.
  • Rausch V, Liu L, Apel A, et al. Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment. J Pathol. 2012;227:325–335.
  • Zhang X, Schonrogge M, Eichberg J, et al. Blocking autophagy in cancer-associated fibroblasts supports chemotherapy of pancreatic cancer cells. Front Oncol. 2018;8:590.
  • Linkermann A, Green DR. Necroptosis. N Engl J Med. 2014;370:455–465.
  • Rickard JA, O’Donnell JA, Evans JM, et al. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell. 2014;157:1175–1188.
  • Goodall ML, Fitzwalter BE, Zahedi S, et al. The autophagy machinery controls cell death switching between apoptosis and necroptosis. Dev Cell. 2016;37:337–349.
  • Seifert L, Werba G, Tiwari S, et al. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature. 2016;532:245–249.
  • Chen C, Xiao W, Huang L, et al. Shikonin induces apoptosis and necroptosis in pancreatic cancer via regulating the expression of RIP1/RIP3 and synergizes the activity of gemcitabine. Am J Transl Res. 2017;9:5507–5517.
  • Xie Y, Zhu S, Zhong M, et al. Inhibition of aurora kinase a induces necroptosis in pancreatic carcinoma. Gastroenterology. 2017;153:1429–43 e5.
  • Liu J, Kuang F, Kroemer G, et al. Autophagy-dependent ferroptosis: machinery and regulation. Cell Chem Biol. 2020;27:420–435.
  • Kang R, Tang D. Autophagy and ferroptosis - what’s the connection? Curr Pathobiol Rep. 2017;5:153–159.
  • Zhou B, Liu J, Kang R, et al. Ferroptosis is a type of autophagy-dependent cell death. Semin Cancer Biol. 2020;66:89–100.
  • Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–1072.
  • Chen X, Li J, Kang R, et al. Ferroptosis: machinery and regulation. Autophagy. 2020;1–28. doi:10.1080/15548627.2020.1810918
  • Kuang F, Liu J, Kang R, et al. Oxidative damage and antioxidant defense in ferroptosis. Front Cell Dev Biol. 2020;8. DOI:10.3389/fcell.2020.586578.
  • Wen Q, Liu J, Kang R, et al. The release and activity of HMGB1 in ferroptosis. Biochem Biophys Res Commun. 2019;510:278–283.
  • Xie Y, Li J, Kang R, et al. Interplay between lipid metabolism and autophagy. Front Cell Dev Biol. 2020;8:431.
  • Hou W, Xie Y, Song X, et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 2016;12:1425–1428.
  • Bai Y, Meng L, Han L, et al. Lipid storage and lipophagy regulates ferroptosis. Biochem Biophys Res Commun. 2019;508:997–1003.
  • Yang M, Chen P, Liu J, et al. Clockophagy is a novel selective autophagy process favoring ferroptosis. Sci Adv. 2019;5:eaaw2238.
  • Liu J, Yang M, Kang R, et al. Autophagic degradation of the circadian clock regulator promotes ferroptosis. Autophagy. 2019;15:2033–2035.
  • Wu Z, Geng Y, Lu X, et al. Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc Natl Acad Sci U S A. 2019;116:2996–3005.
  • Dai E, Han L, Liu J, et al. Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein. Autophagy. 2020; 16:2069–2083
  • Wang H, Liu C, Zhao Y, et al. Inhibition of LONP1 protects against erastin-induced ferroptosis in Pancreatic ductal adenocarcinoma PANC1 cells. Biochem Biophys Res Commun. 2020;522:1063–1068.
  • Daher B, Parks SK, Durivault J, et al. Genetic ablation of the cystine transporter xCT in PDAC cells inhibits mTORC1, growth, survival, and tumor formation via nutrient and oxidative stresses. Cancer Res. 2019;79:3877–3890.
  • Badgley MA, Kremer DM, Maurer HC, et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science. 2020;368:85–89.
  • Wang Y, Liua Y, Liua J, et al. NEDD4L-mediated LTF protein degradation limits ferroptosis. Biochem Biophys Res Commun. 2020; 531:581–587
  • Wang K, Zhang Z, Wang M, et al. Role of GRP78 inhibiting artesunate-induced ferroptosis in KRAS mutant pancreatic cancer cells. Drug Des Devel Ther. 2019;13:2135–2144.
  • Eling N, Reuter L, Hazin J, et al. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience. 2015;2:517–532.
  • Xie Y, Kuang F, Liu J, et al. DUSP1 blocks autophagy-dependent ferroptosis in pancreatic cancer. J pancreatol. 2020;3:154–160. DOI:10.1097/JP9.0000000000000054.
  • Chen X, Xu C, Kang R, et al. Iron metabolism in ferroptosis. Front Cell Dev Biol. 2020;8:1–14.
  • Li C, Zhang Y, Liu J, et al. Mitochondrial DNA stress triggers autophagy-dependent ferroptotic death. Autophagy. 2020; Mar 18; 1–13. doi:10.1080/15548627.2020.1739447
  • Kuang F, Liu J, Li C, et al. Cathepsin B is a mediator of organelle-specific initiation of ferroptosis. Biochem Biophys Res Commun. 2020. DOI:10.1016/j.bbrc.2020.10.035
  • Zhu S, Zhang Q, Sun X, et al. HSPA5 regulates ferroptotic cell death in cancer cells. Cancer Res. 2017;77:2064–2077.
  • Liu Y, Wang Y, Liu J, et al. Interplay between MTOR and GPX4 signaling modulates autophagy-dependent ferroptotic cancer cell death. Cancer Gene Ther. 2020. DOI:10.1038/s41417-020-0182-y
  • Garcia-Lora A, Algarra I, Garrido F. MHC class I antigens, immune surveillance, and tumor immune escape. J Cell Physiol. 2003;195:346–355.
  • Patel SA, Minn AJ. Combination cancer therapy with immune checkpoint blockade: mechanisms and strategies. Immunity. 2018;48:417–433.
  • Yamamoto K, Venida A, Yano J, et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature. 2020;581:100–105.
  • Yang YH, Liu JB, Gui Y, et al. Relationship between autophagy and perineural invasion, clinicopathological features, and prognosis in pancreatic cancer. World J Gastroenterol. 2017;23:7232–7241.
  • Kong C, Li Y, Liu Z, et al. Targeting the oncogene KRAS mutant pancreatic cancer by synergistic blocking of lysosomal acidification and rapid drug release. ACS Nano. 2019;13:4049–4063.
  • Li X, Zhu F, Jiang J, et al. Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells. Autophagy. 2016;12:1521–1537.
  • Awale S, Dibwe DF, Balachandran C, et al. Ancistrolikokine E3, a 5,8ʹ-coupled naphthylisoquinoline alkaloid, eliminates the tolerance of cancer cells to nutrition starvation by inhibition of the akt/mtor/autophagy signaling pathway. J Nat Prod. 2018;81:2282–2291.
  • Yu Z, Yu Z, Chen Z, et al. Zinc chelator TPEN induces pancreatic cancer cell death through causing oxidative stress and inhibiting cell autophagy. J Cell Physiol. 2019;234:20648–20661.
  • Nordstrom LU, Sironi J, Aranda E, et al. Discovery of autophagy inhibitors with antiproliferative activity in lung and pancreatic cancer cells. ACS Med Chem Lett. 2015;6:134–139.
  • Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol. 2008;15:234–245.
  • Rickmann M, Vaquero EC, Malagelada JR, et al. Tocotrienols induce apoptosis and autophagy in rat pancreatic stellate cells through the mitochondrial death pathway. Gastroenterology. 2007;132:2518–2532.
  • Vaquero EC, Rickmann M, Molero X. Tocotrienols: balancing the mitochondrial crosstalk between apoptosis and autophagy. Autophagy. 2007;3:652–654.
  • Newman RA, Kondo Y, Yokoyama T, et al. Autophagic cell death of human pancreatic tumor cells mediated by oleandrin, a lipid-soluble cardiac glycoside. Integr Cancer Ther. 2007;6:354–364.
  • Du J, Martin SM, Levine M, et al. Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin Cancer Res. 2010;16:509–520.
  • Mujumdar N, Mackenzie TN, Dudeja V, et al. Triptolide induces cell death in pancreatic cancer cells by apoptotic and autophagic pathways. Gastroenterology. 2010;139:598–608.
  • Singh BN, Kumar D, Shankar S, et al. Rottlerin induces autophagy which leads to apoptotic cell death through inhibition of PI3K/Akt/mTOR pathway in human pancreatic cancer stem cells. Biochem Pharmacol. 2012;84:1154–1163.
  • Shen Q, Wang J, Liu CX, et al. Synthesis and evaluation of tetrahydroquinolin-2(1H)-one derivatives as novel anti-pancreatic cancer agents via targeting autophagy. Eur J Med Chem. 2019;170:28–44.
  • Li C, Xu H, Chen X, et al. Aqueous extract of clove inhibits tumor growth by inducing autophagy through AMPK/ULK pathway. Phytother Res. 2019;33:1794–1804.
  • Fukui M, Yamabe N, Choi HJ, et al. Mechanism of ascorbate-induced cell death in human pancreatic cancer cells: role of bcl-2, beclin 1 and autophagy. Planta Med. 2015;81:838–846.
  • Pathania AS, Guru SK, Kumar S, et al. Interplay between cell cycle and autophagy induced by boswellic acid analog. Sci Rep. 2016;6:33146.
  • Dando I, Donadelli M, Costanzo C, et al. Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells. Cell Death Dis. 2013;4:e664.
  • Li H, Chen H, Li R, et al. Cucurbitacin I induces cancer cell death through the endoplasmic reticulum stress pathway. J Cell Biochem. 2018. doi:10.1002/jcb.27570
  • Ovadje P, Chochkeh M, Akbari-Asl P, et al. Selective induction of apoptosis and autophagy through treatment with dandelion root extract in human pancreatic cancer cells. Pancreas. 2012;41:1039–1047.
  • Zhang X, Hu P, Ding SY, et al. Induction of autophagy-dependent apoptosis in cancer cells through activation of ER stress: an uncovered anti-cancer mechanism by anti-alcoholism drug disulfiram. Am J Cancer Res. 2019;9:1266–1281.
  • Krishan S, Sahni S, Leck LYW, et al. Regulation of autophagy and apoptosis by Dp44mT-mediated activation of AMPK in pancreatic cancer cells. Biochim Biophys Acta Mol Basis Dis. 2020;1866:165657.
  • Jia S, Xu X, Zhou S, et al. Fisetin induces autophagy in pancreatic cancer cells via endoplasmic reticulum stress- and mitochondrial stress-dependent pathways. Cell Death Dis. 2019;10:142.
  • Pardo R, Lo Re A, Archange C, et al. Gemcitabine induces the VMP1-mediated autophagy pathway to promote apoptotic death in human pancreatic cancer cells. Pancreatology. 2010;10:19–26.
  • Akimoto M, Iizuka M, Kanematsu R, et al. Anticancer effect of ginger extract against pancreatic cancer cells mainly through reactive oxygen species-mediated autotic cell death. PLoS One. 2015;10:e0126605.
  • Liu L, Zhang N, Dou Y, et al. Lysosomal dysfunction and autophagy blockade contribute to IMB-6G-induced apoptosis in pancreatic cancer cells. Sci Rep. 2017;7:41862.
  • Yu M, Nguyen ND, Huang Y, et al. Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer. JCI Insight. 2019;5:e126915
  • Xu C, Wang Y, Tu Q, et al. Targeting surface nucleolin induces autophagy-dependent cell death in pancreatic cancer via AMPK activation. Oncogene. 2019;38:1832–1844.
  • Gomez de Cedron M, Mouhid L, Garcia-Carrascosa E, et al. Marigold supercritical extract as potential co-adjuvant in pancreatic cancer: the energetic catastrophe induced via bmp8b ends up with autophagy-induced cell death. Front Bioeng Biotechnol. 2019;7:455.
  • Cho YR, Lee JH, Kim JH, et al. Matrine suppresses KRAS-driven pancreatic cancer growth by inhibiting autophagy-mediated energy metabolism. Mol Oncol. 2018;12:1203–1215.
  • Millet A, Plaisant M, Ronco C, et al. Discovery and Optimization of N-(4-(3-Aminophenyl)thiazol-2-yl)acetamide as a Novel Scaffold Active against Sensitive and Resistant Cancer Cells. J Med Chem. 2016;59:8276–8292.
  • Liu W, Wang X, Sun J, et al. Parthenolide suppresses pancreatic cell growth by autophagy-mediated apoptosis. Onco Targets Ther. 2017;10:453–461.
  • Ranjan A, Srivastava SK. Penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis. Sci Rep. 2016;6:26165.
  • Liao G, Gao B, Gao Y, et al. Phycocyanin inhibits tumorigenic potential of pancreatic cancer cells: role of apoptosis and autophagy. Sci Rep. 2016;6:34564.
  • Ogata A, Yanagie H, Ishikawa E, et al. Antitumour effect of polyoxomolybdates: induction of apoptotic cell death and autophagy in in vitro and in vivo models. Br J Cancer. 2008;98:399–409.
  • Bello C, Bai J, Zambron BK, et al. Induction of cell killing and autophagy by amphiphilic pyrrolidine derivatives on human pancreatic cancer cells. Eur J Med Chem. 2018;150:457–478.
  • Dai ZJ, Gao J, Ma XB, et al. Antitumor effects of rapamycin in pancreatic cancer cells by inducing apoptosis and autophagy. Int J Mol Sci. 2012;14:273–285.
  • Li X, Xu H, Li C, et al. Zinc-doped copper oxide nanocomposites inhibit the growth of pancreatic cancer by inducing autophagy through AMPK/mTOR pathway. Front Pharmacol. 2019;10:319.
  • Li X, Roife D, Kang Y, et al. Extracellular lumican augments cytotoxicity of chemotherapy in pancreatic ductal adenocarcinoma cells via autophagy inhibition. Oncogene. 2016;35:4881–4890.
  • Rebecca VW, Nicastri MC, McLaughlin N, et al. A unified approach to targeting the lysosome’s degradative and growth signaling roles. Cancer Discov. 2017;7:1266–1283.
  • Kasukabe T, Honma Y, Okabe-Kado J, et al. Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells. Oncol Rep. 2016;36:968–976.
  • Vitale G, Zappavigna S, Marra M, et al. The PPAR-gamma agonist troglitazone antagonizes survival pathways induced by STAT-3 in recombinant interferon-beta treated pancreatic cancer cells. Biotechnol Adv. 2012;30:169–184.
  • Xu XD, Zhao Y, Zhang M, et al. Inhibition of autophagy by deguelin sensitizes pancreatic cancer cells to doxorubicin. Int J Mol Sci. 2017;18:370
  • Fiorini C, Menegazzi M, Padroni C, et al. Autophagy induced by p53-reactivating molecules protects pancreatic cancer cells from apoptosis. Apoptosis. 2013;18:337–346.
  • Yuan Y, Tang AJ, Castoreno AB, et al. Gossypol and an HMT G9a inhibitor act in synergy to induce cell death in pancreatic cancer cells. Cell Death Dis. 2013;4:e690.
  • He R, Shi X, Zhou M, et al. Alantolactone induces apoptosis and improves chemosensitivity of pancreatic cancer cells by impairment of autophagy-lysosome pathway via targeting TFEB. Toxicol Appl Pharmacol. 2018;356:159–171.
  • Xu C, Wang X, Zhou Y, et al. Synergy between arsenic trioxide and JQ1 on autophagy in pancreatic cancer. Oncogene. 2019;38:7249–7265.
  • Donadelli M, Dando I, Zaniboni T, et al. Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism. Cell Death Dis. 2011;2:e152.
  • Sleightholm R, Yang B, Yu F, et al. Chloroquine-modified hydroxyethyl starch as a polymeric drug for cancer therapy. Biomacromolecules. 2017;18:2247–2257.
  • Zhang X, Kumstel S, Jiang K, et al. LW6 enhances chemosensitivity to gemcitabine and inhibits autophagic flux in pancreatic cancer. J Adv Res. 2019;20:9–21.
  • Mukai S, Moriya S, Hiramoto M, et al. Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines. Int J Oncol. 2016;48:45–54.
  • Chen CH, Hsieh TH, Lin YC, et al. Targeting autophagy by MPT0L145, a highly potent PIK3C3 Inhibitor, provides synergistic interaction to targeted or chemotherapeutic agents in cancer cells. Cancers (Basel). 2019;11:1345
  • Wu Y, Tang Y, Xie S, et al. Chimeric peptide supramolecular nanoparticles for plectin-1 targeted miRNA-9 delivery in pancreatic cancer. Theranostics. 2020;10:1151–1165.
  • Chen W, Zhou Y, Zhi X, et al. Delivery of miR-212 by chimeric peptide-condensed supramolecular nanoparticles enhances the sensitivity of pancreatic ductal adenocarcinoma to doxorubicin. Biomaterials. 2019;192:590–600.
  • Lan CY, Chen SY, Kuo CW, et al. Quercetin facilitates cell death and chemosensitivity through RAGE/PI3K/AKT/mTOR axis in human pancreatic cancer cells. J Food Drug Anal. 2019;27:887–896.
  • Zhao C, He R, Shen M, et al. PINK1/parkin-mediated mitophagy regulation by reactive oxygen species alleviates rocaglamide a-induced apoptosis in pancreatic cancer cells. Front Pharmacol. 2019;10:968.
  • Thakur PC, Miller-Ocuin JL, Nguyen K, et al. Inhibition of endoplasmic-reticulum-stress-mediated autophagy enhances the effectiveness of chemotherapeutics on pancreatic cancer. J Transl Med. 2018;16:190.
  • Lund K, Olsen CE, Wong JJW, et al. 5-FU resistant EMT-like pancreatic cancer cells are hypersensitive to photochemical internalization of the novel endoglin-targeting immunotoxin CD105-saporin. J Exp Clin Cancer Res. 2017;36:187.
  • Chen X, Yu Q, Liu Y, et al. Synergistic cytotoxicity and co-autophagy inhibition in pancreatic tumor cells and cancer-associated fibroblasts by dual functional peptide-modified liposomes. Acta Biomater. 2019;99:339–349.
  • Lin JH, Chen SY, Lu CC, et al. Ursolic acid promotes apoptosis, autophagy, and chemosensitivity in gemcitabine-resistant human pancreatic cancer cells. Phytother Res. 2020;34:2053–2066.
  • Elliott IA, Dann AM, Xu S, et al. Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion. Proc Natl Acad Sci U S A. 2019;116:6842–6847.
  • Donohue E, Thomas A, Maurer N, et al. The autophagy inhibitor verteporfin moderately enhances the antitumor activity of gemcitabine in a pancreatic ductal adenocarcinoma model. J Cancer. 2013;4:585–596.
  • Ma T, Chen W, Zhi X, et al. USP9X inhibition improves gemcitabine sensitivity in pancreatic cancer by inhibiting autophagy. Cancer Lett. 2018;436:129–138.
  • Mirzoeva OK, Hann B, Hom YK, et al. Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K-mTOR pathway in pancreatic adenocarcinoma. J Mol Med (Berl). 2011;89:877–889.
  • Wang F, Tian X, Zhang Z, et al. Demethylzeylasteral (ZST93) inhibits cell growth and enhances cell chemosensitivity to gemcitabine in human pancreatic cancer cells via apoptotic and autophagic pathways. Int J Cancer. 2018;142:1938–1951.
  • Dai ZJ, Gao J, Kang HF, et al. Targeted inhibition of mammalian target of rapamycin (mTOR) enhances radiosensitivity in pancreatic carcinoma cells. Drug Des Devel Ther. 2013;7:149–159.
  • Wang F, Xia X, Yang C, et al. SMAD4 gene mutation renders pancreatic cancer resistance to radiotherapy through promotion of autophagy. Clin Cancer Res. 2018;24:3176–3185.
  • Wang P, Zhang J, Zhang L, et al. MicroRNA 23b regulates autophagy associated with radioresistance of pancreatic cancer cells. Gastroenterology. 2013;145:1133–43 e12.
  • Koshkina NV, Briggs K, Palalon F, et al. Autophagy and enhanced chemosensitivity in experimental pancreatic cancers induced by noninvasive radiofrequency field treatment. Cancer. 2014;120:480–491.
  • Mukubou H, Tsujimura T, Sasaki R, et al. The role of autophagy in the treatment of pancreatic cancer with gemcitabine and ionizing radiation. Int J Oncol. 2010;37:821–828.
  • Chiu HW, Lin SW, Lin LC, et al. Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6. Cancer Lett. 2015;365:229–239.
  • Aravindan S, Ramraj SK, Somasundaram ST, et al. Novel adjuvants from seaweed impede autophagy signaling in therapy-resistant residual pancreatic cancer. J Biomed Sci. 2015;22:28.
  • Chude CI, Amaravadi RK. Targeting autophagy in cancer: update on clinical trials and novel inhibitors. Int J Mol Sci. 2017;18:1279
  • Boone BA, Bahary N, Zureikat AH, et al. Safety and biologic response of pre-operative autophagy inhibition in combination with gemcitabine in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2015;22:4402–4410.
  • Zeh H, Bahary N, Boone BA, et al. A randomized phase II preoperative study of autophagy inhibition with high-dose hydroxychloroquine and gemcitabine/nab-paclitaxel in pancreatic cancer patients. Clin Cancer Res. 2020;26:3126–3134.
  • Karasic TB, O’Hara MH, Loaiza-Bonilla A, et al. Effect of gemcitabine and nab-paclitaxel with or without hydroxychloroquine on patients with advanced pancreatic cancer: a phase 2 randomized clinical trial. JAMA Oncol. 2019;5:993–998.
  • Kinzya Grant HZ, Miller J, Laymon C, et al. FDG PET analysis of treatment response in patients with pancreatic adenocarcinoma randomized to preoperative therapy with or without hydroxychloroquine. J Nucl Med. 2015;56:1408
  • Wolpin BM, Rubinson DA, Wang X, et al. Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. Oncologist. 2014;19:637–638.

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