A new pancreatic adenocarcinoma-derived organoid model of acquired chemoresistance to FOLFIRINOX: First insight of the underlying mechanisms.
Cancer
Cell death
Oncology/cancer
Pancreas
Journal
Biology of the cell
ISSN: 1768-322X
Titre abrégé: Biol Cell
Pays: England
ID NLM: 8108529
Informations de publication
Date de publication:
Jan 2022
Jan 2022
Historique:
revised:
02
09
2021
received:
21
01
2021
accepted:
02
09
2021
pubmed:
26
9
2021
medline:
14
1
2022
entrez:
25
9
2021
Statut:
ppublish
Résumé
Although improvements have been made in the management of pancreatic adenocarcinoma (PDAC) during the past 20 years, the prognosis of this deadly disease remains poor with an overall 5-year survival under 10%. Treatment with FOLFIRINOX, a combined regimen of 5-fluorouracil, irinotecan (SN-38) and oxaliplatin, is nonetheless associated with an excellent initial tumour response and its use has allowed numerous patients to go through surgery while their tumour was initially considered unresectable. These discrepancies between initial tumour response and very low long-term survival are the consequences of rapidly acquired chemoresistance and represent a major therapeutic frontier. To our knowledge, a model of resistance to the combined three drugs has never been described due to the difficulty of modelling the FOLFIRINOX protocol both in vitro and in vivo. Patient-derived tumour organoids (PDO) are the missing link that has long been lacking in the wide range of epithelial cancer models between 2D adherent cultures and in vivo xenografts. In this work we sought to set up a model of PDO with resistance to FOLFIRINOX regimen that we could compare to the paired naive PDO. We first extrapolated physiological concentrations of the three drugs using previous pharmacodynamics studies and bi-compartmental elimination models of oxaliplatin and SN-38. We then treated PaTa-1818x naive PDAC organoids with six cycles of 72 h-FOLFIRINOX treatment followed by 96 h interruption. Thereafter, we systematically compared treated organoids to PaTa-1818x naive organoids in terms of growth, proliferation, viability and expression of genes involved in cancer stemness and aggressiveness. We reproductively obtained resistant organoids FoxR that significantly showed less sensitivity to FOLFORINOX treatment than the PaTa-1818x naive organoids from which they were derived. Our resistant model is representative of the sequential steps of chemoresistance observed in patients in terms of growth arrest (proliferation blockade), residual disease (cell quiescence/dormancy) and relapse. To our knowledge, this is the first genuine in vitro model of resistance to the three drugs in combined therapy. This new PDO model will be a great asset for the discovery of acquired chemoresistance mechanisms, knowledge that is mandatory before offering new therapeutic strategies for pancreatic cancer.
Sections du résumé
BACKGROUND INFORMATION
BACKGROUND
Although improvements have been made in the management of pancreatic adenocarcinoma (PDAC) during the past 20 years, the prognosis of this deadly disease remains poor with an overall 5-year survival under 10%. Treatment with FOLFIRINOX, a combined regimen of 5-fluorouracil, irinotecan (SN-38) and oxaliplatin, is nonetheless associated with an excellent initial tumour response and its use has allowed numerous patients to go through surgery while their tumour was initially considered unresectable. These discrepancies between initial tumour response and very low long-term survival are the consequences of rapidly acquired chemoresistance and represent a major therapeutic frontier. To our knowledge, a model of resistance to the combined three drugs has never been described due to the difficulty of modelling the FOLFIRINOX protocol both in vitro and in vivo. Patient-derived tumour organoids (PDO) are the missing link that has long been lacking in the wide range of epithelial cancer models between 2D adherent cultures and in vivo xenografts. In this work we sought to set up a model of PDO with resistance to FOLFIRINOX regimen that we could compare to the paired naive PDO.
RESULTS
RESULTS
We first extrapolated physiological concentrations of the three drugs using previous pharmacodynamics studies and bi-compartmental elimination models of oxaliplatin and SN-38. We then treated PaTa-1818x naive PDAC organoids with six cycles of 72 h-FOLFIRINOX treatment followed by 96 h interruption. Thereafter, we systematically compared treated organoids to PaTa-1818x naive organoids in terms of growth, proliferation, viability and expression of genes involved in cancer stemness and aggressiveness.
CONCLUSIONS
CONCLUSIONS
We reproductively obtained resistant organoids FoxR that significantly showed less sensitivity to FOLFORINOX treatment than the PaTa-1818x naive organoids from which they were derived. Our resistant model is representative of the sequential steps of chemoresistance observed in patients in terms of growth arrest (proliferation blockade), residual disease (cell quiescence/dormancy) and relapse.
SIGNIFICANCE
CONCLUSIONS
To our knowledge, this is the first genuine in vitro model of resistance to the three drugs in combined therapy. This new PDO model will be a great asset for the discovery of acquired chemoresistance mechanisms, knowledge that is mandatory before offering new therapeutic strategies for pancreatic cancer.
Identifiants
pubmed: 34561874
doi: 10.1111/boc.202100003
doi:
Substances chimiques
folfirinox
0
Oxaliplatin
04ZR38536J
Irinotecan
7673326042
Leucovorin
Q573I9DVLP
Fluorouracil
U3P01618RT
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
32-55Subventions
Organisme : Centre hospitalier régional universitaire de Lille
Organisme : Fondation ARC pour la Recherche sur le Cancer
Organisme : Institut National Du Cancer
ID : 6041
Organisme : Région Hauts-de-France
ID : CPER Cancer 2007-2013
Organisme : Région Hauts-de-France
ID : CPER Cancer 2015-2020
Organisme : Université de Lille
Organisme : Ligue Contre le Cancer - Comité du Nord
Organisme : Canceropôle Nord-Ouest
Organisme : Institut National de la Santé et de la Recherche Médicale
Informations de copyright
© 2021 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.
Références
Ahmed, F., Vyas, V., Cornfield, A., Goodin, S., Ravikumar, T.S. Rubin, E.H. & Gupta, E. (1999) In vitro activation of irinotecan to SN-38 by human liver and intestine. Anticancer Research, 19, 2067-2071.
Amours, D.D., Sallmann, F.R., Dixit, V.M. & Poirier, G.G. (2001) Gain-of-function of poly(ADP-ribose) polymerase-1 upon cleavage by apoptotic proteases: implications for apoptosis. Journal of Cell Science, 114, 3771-3778.
Amsterdam, A., Raanan, C., Schreiber, L., Polin, N. & Givol, D. (2013) Biochemical and biophysical research communications LGR5 and Nanog identify stem cell signature of pancreas beta cells which initiate pancreatic cancer. Biochemical and Biophysical Research Communications, 433(2), 157-162.
Andrikou, K., Santoni, M., Piva, F., Bittoni, A., Lanese, A., Pellei, C., Conti, A., Loretelli, C., Mandolesi, A., Giulietti, M., Scarpelli, M., Principato, G., Falconi, M. & Cascinu, S. (2015) Lgr5 expression, cancer stem cells and pancreatic cancer: results from biological and computational analyses. Future Oncology, 11, 1037-1045.
Baker, L.A., Tiriac, H., Clevers, H. & Tuveson, D.A. (2016) Modeling pancreatic cancer with organoids. Trends in Cancer, 2(4), 176-190.
Balak, J.R.A., Juksar, J., Carlotti, F., Nigro, A.Lo & Koning, E.J.P.D. (2019) Organoids from the human fetal and adult pancreas. Current Diabetes Reports, 19, 160.
Begicevic, R.R & Falasca, M. (2017) ABC Transporters in cancer stem cells: beyond chemoresistance. International Journal of Molecular Sciences, 18, 2362.
Beumer, J. & Clevers, H. (2016) Regulation and plasticity of intestinal stem cells during homeostasis and regeneration. 3639-3649.
Bleijs, M., Wetering, M., Clevers, H. & Drost, J. (2019) Xenograft and organoid model systems in cancer research. Embo Journal, 38(15), 1-11.
Boj, S.F., Hwang, C.-I., Baker, L.A., Chio, I.I.C., Engle, D.D., Corbo, V., Jager, M., Ponz-Sarvise, M., Tiriac, H., Spector, M.S., Gracanin, A., Oni, T., Yu, K.H., Van Boxtel, R., Huch, M., Rivera, K.D., Wilson, J.P., Feigin, M.E., Öhlund, D., Handly-Santana, A., Ardito-Abraham, C.M., Ludwig, M., Elyada, E., Alagesan, B., Biffi, G., Yordanov, G.N., Delcuze, B., Creighton, B., Wright, K., Park, Y., Morsink, F.H.M., Molenaar, I.Q., Borel Rinkes, I.H., Cuppen, E., Hao, Y., Jin, Y., Nijman, I.J., Iacobuzio-Donahue, C., Leach, S.D., Pappin, D.J., Hammell, M., Klimstra, D.S., Basturk, O., Hruban, R.H., Offerhaus, G.J., Vries, R.G.J., Clevers, H. & Tuveson, D.A. (2015) Resource organoid models of human and mouse ductal pancreatic cancer. Cell, 160, 324-338.
Castrogiovanni, C., Waterschoot, B., De Backer, O. & Dumont, P. (2018) Serine 392 phosphorylation modulates p53 mitochondrial translocation and transcription independent apoptosis. Cell Death and Differentiation, 25(1), 1-14.
Chen, L., Manautou, J.E. & Rasmussen, T.P. (2019) Development of precision medicine approaches based on inter-individual variability of BCRP /ABCG2. Acta Pharmaceutica Sinica B, 9(4), 659-674.
Conroy, T., Desseigne, F., Ychou, M., Bouché, O., Guimbaud, R., Bécouarn, Y., Adenis, A., Raoul, J.-.L., Gourgou-Bourgade, S., De La Fouchardière, C., Bennouna, J., Bachet, J.-.B., Khemissa-Akouz, F., Péré-Vergé, D., Delbaldo, C., Assenat, E., Chauffert, B., Michel, P., Montoto-Grillot, C. & Ducreux, M. (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. The New England Journal of Medicine, 364;19.
Conroy, T., Hammel, P., Hebbar, M., Abdelghani, M.B, Wei, A.C., Raoul, J., Choné, L., Francois, E., Artru, P., Biagi, J.J., Lecomte, T., Assenat, E., Faroux, R., Ychou, M., Volet, J., Sauvanet, A., Breysacher, G., Fiore, F.D., Cripps, C., Kavan, P., Texereau, P., Bouhier-Leporrier, K., Khemissa-Akouz, F., Legoux, J.-L. & Juzyna , B. (2018) FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. The New England Journal of Medicine, 379;25.
De Man, FM., Goey, A.K.L. & Van Schaik, R.H.N. (2018) Individualization of Irinotecan treatment : a review of pharmacokinetics, pharmacodynamics, and pharmacogenetics. Clinical Pharmacokinetics, 57(10):1229-1254.
Descarpentries, C., Leprêtre, F., Sebda, S., Baldacci, S. & Grégoire, V. (2018) Optimization of routine testing for MET Exon 14 splice site mutations in NSCLC patients. Journal of Thoracic Oncology, 13(12), 1873-1883.
Deyme, L., Barbolosi, D. & Gattacceca, F. (2019) Population pharmacokinetics of FOLFIRINOX: a review of studies and parameters. Cancer Chemotherapy and Pharmacology, 83, 27-42.
El Amrani, M., Corfiotti, F., Corvaisier, M., Vasseur, R., Fulbert, M., Skrzypczyk, C., Deshorgues, A.-.C., Gnemmi, V., Tulasne, D., Lahdaoui, F., Vincent, A., Pruvot, F.-.R., Seuningen, I., Huet, G. & Truant, S. (2019) Gemcitabine - induced epithelial - mesenchymal transition - like changes sustain chemoresistance of pancreatic cancer cells of mesenchymal - like phenotype. Molecular Carcinogenesis, 58(11), 1985-1997.
Ercan, G., Karlitepe, A. & Ozpolat, B. (2017) Pancreatic cancer stem cells and therapeutic approaches. Anticancer Research, 37, 2761-2775.
Erenpreisa, J. & Cragg, M.S. (2013) Three steps to the immortality of cancer cells : senescence, polyploidy and self-renewal. Cancer Cell International, 13(1), 1.
Faubert, B., Boily, G., Izreig, S., Griss, T., Samborska, B., Dong, Z., Dupuy, F., Chambers, C., Fuerth, B.J., Viollet, B., Mamer, O.A., Avizonis, D., DeBerardinis, R.J., Siegel, P.M. & Jones, R.G. (2013) Article ampk is a negative regulator of the warburg effect and suppresses tumor growth in vivo. CMET, 17(1), 113-124.
Fujii, M. & Sato, T. (2021) Somatic cell-derived organoids as prototypes of human epithelial tissues and diseases. Nat. Mater, 20, 156-169. https://doi.org/10.1038/s41563-020-0754-0
Guo, X., Goessl, E., Jin, G., Collie-duguid, E.S.R., Cassidy, J., Wang, W. & Brien, V.O. (2008) Cell cycle perturbation and acquired 5-fluorouracil chemoresistance, Anticancer Research, 28, 9-14.
Harada, H., Andersen, J.S., Mann, M., Terada, N. & Korsmeyer, S.J. (2001) p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proceedings of the National Academy of Sciences of the United States of America, 98(17), 9666-9670.
Hof, L., Moreth, T., Koch, M., Liebisch, T., Kurtz, M., Tarnick, J., Lissek, S.M., Verstegen, M.M.A., van der Laan, L.J.W., Huch, M., Matthäus, F., Stelzer, E.H.K. & Pampaloni, F. (2021) Long-term live imaging and multiscale analysis identify heterogeneity and core principles of epithelial organoid morphogenesis. Bmc Biology, 1-22.
Huch, M., Bonfanti, P., Boj, S.F., Sato, T., Loomans, C.J.M., Van De Wetering, M., Sojoodi, M., Li, V.S.W., Schuijers, J., Gracanin, A., Ringnalda, F., Begthel, H., Hamer, K., Mulder, J., Van Es, J.H., De Koning, E., Vries, R.G.J., Heimberg, H. & Clevers, H. (2013) Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5 /R-spondin axis. Embo Journal, 32(20), 2708-2721.
Kaufmann, S.H., Desnoyers, S., Ottaviano, Y., Davidson, N.E. & Poirier, G.G. (1993) Specific proteolytic cleavage of Poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Research, 53(17), 3976-3985.
Lee, S.H., Kim, H. & Hwang, J. (2014) CD24 and S100A4 expression in resectable pancreatic cancers with earlier disease recurrence and poor survival. Pancreas Journals, 43(3), 380-388.
Leushacke, M. & Barker, N. (2012) Lgr5 and Lgr6 as markers to study adult stem cell roles in self-renewal and cancer. Oncogene, 3009-3022.
Loomans, C., Giuliani, N.W., Balak, J., Ringnalda, F., Van Gurp, L., Huch, M., Boj, S.F., Sato, T., Kester, L., Lopes, S.M.C.S., Roost, M.S., Bonner-Weir, S., Engelse, M.A., Rabelink, T.J., Heimberg, H., Vries, R.G.J., Oudenaarden, A., Carlotti, F., Clevers, H. & de Koning, E.J.P. (2018) Expansion of adult human pancreatic tissue yields organoids harboring progenitor cells with endocrine differentiation potential. Stem Cell Reports, 10(13), 712-724.
Mahon, P.C., Baril, P., Bhakta, V., Chelala, C., Caulee, K., Harada, T. & Lemoine, N.R. (2007) S100A4 contributes to the suppression of BNIP3 expression, chemoresistance, and inhibition of apoptosis in pancreatic cancer. Cancer Research, (14), 6786-6796.
Mathijssen, R.H.J., Robbert, J., van Alphen, Verweij, J., Loos, W.J., Nooter, K., Stoter, G. & Sparreboom, A. (2001) Clinical pharmacokinetics and metabolism of nimesulide. Inflammopharmacology, 9(1-2):81-89.
Mizrahi, J.D., Surana, R., Valle, J.W. & Shroff, R.T. (2020) Pancreatic cancer. The Lancet, 395(10242), 2008-2020.
Moon, H.H., Kim, S.H. & Ku, J.L. (2015) Correlation between the promoter methylation status of ATP-binding cassette sub-family G member 2 and drug sensitivity in colorectal cancer cell lines. Oncology Reports, 35(1), 298-306.
Muriithi, W., Macharia, L.W., Heming, C.P., Echevarria, J.L., Filho, P.N. & Neto, V.M. (2020) REVIEW ABC transporters and the hallmarks of cancer: roles in cancer aggressiveness beyond multidrug resistance ABC proteins: structure and function dynamics. Cancer Biology & Medicine, 17: 253-269.
Murphy, J.E., Wo, J.Y. & Ryan, D.P.(2018) Total Neoadujuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for bordeline resectable pancreatic adenocarcinoma. JAMA oncology. 4(7), 963-969
Nagle, P.W., Plukker, J.T.M., Muijs, C.T., van Luijk, P. & Coppes, R.P. (2018) Patient-derived tumor organoids for prediction of cancer treatment response. Seminars in Cancer Biolog, 53(May), 258-264.
Nastase, A., Dima, S., Tica, V., Florea, R., Sorop, A., Ilie, V., Eftimie, M., Paslaru, L., Herlea, V., Bacalbaşa, N., Ivan, L., Uyy, E., Iulian Suica, V., Antohe, F., Iancu, I.V., Plesa, A., Botezatu, A., Duda, D.G. & Diaconu, C.C. (2016) S100A4 and ERBB2 as co-factors in pancreatic cancer. Journal of Translational Medicine, 21(4), 259-266.
Pasch, C.A., Favreau, P.F., Yueh, A.E., Babiarz, C.P., Gillette, A.A., Sharick, J.T., Karim, M.R., Nickel, K.P., Dezeeuw, A.K., Sprackling, C.M., Emmerich, P.B., Destefanis, R.A., Pitera, R.T., Payne, S.N., Korkos, D.P., Clipson, L., Walsh, C.M., Miller, D., Carchman, E.H., Burkard, M.E., Lemmon, K.K., Matkowskyj, K.A., Newton, M.A., Ong, I.M., Bassetti, M.F., Kimple, R.J., Skala, M.C., & Deming, D.A. (2019) Patient-derived cancer organoid cultures to predict sensitivity to chemotherapy and radiation. Clinical Cancer Research, 25(17), 5376-5387.
Podhorecka, M., Skladanowski, A. & Bozko, P. (2010) H2AX phosphorylation: its role in DNA damage response and cancer therapy. Journal of Nucleic Acids, 2010.
Praharaj, P.P., Bhutia, S.K., Nagrath, S., Bitting, R.L. & Deep, G. (2018) Circulating tumor cell-derived organoids: current challenges and promises in medical research and precision medicine. Biochimica et Biophysica Acta - Reviews on Cancer, 1869(2), 117-127.
Rahib, L., Smith, B.D., Aizenberg, R., Rosenzweig, A.B., Fleshman, J.M. & Matrisian, L.M. (2014) Projecting cancer incidence and deaths to 2030 : the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Research, 74, 2913-2921.
Romero-Calvo, I., Weber, C.R., Ray, M., Brown, M., Kirby, K., Nandi, R.K., Long, T.M., Sparrow, S.M., Ugolkov, A., Qiang, W., Zhang, Y., Brunetti, T., Kindler, H., Segal, J.P., Rzhetsky, A., Mazar, A.P., Buschmann, M.M., Weichselbaum, R., Roggin, K. & White, K.P. (2019) Human organoids share structural and genetic features with primary pancreatic adenocarcinoma tumors. Molecular Cancer Research, 17(1), 70-83.
Rosner, G.L., Panetta, J.C., Innocenti, F. & Ratain, M.J. (2008) pharmacogenetic pathway analysis of Irinotecan, Clinical Pharmacology and Therapeutics, 84(3), 393-402.
Rosty, C., Ueki, T., Argani, P., Jansen, M., Yeo, C.J., Cameron, J.L., Hruban, R.H. & Goggins, M. (2002) Overexpression of S100A4 in pancreatic ductal adenocarcinomas is associated with poor differentiation and DNA hypomethylation. AJP, 160(1), 45-50.
Sasaki, N., Ishiwata, T., Hasegawa, F., Michishita, M., Kawai, H., Matsuda, Y., Arai, T., Ishikawa, N., Aida, J., Takubo, K. & Toyoda, M. (2018) Stemness and anti-cancer drug resistance in ATP-binding cassette subfamily G member 2 highly expressed pancreatic cancer is induced in 3D culture conditions. Cancer Science, 109(4), 1135-1146.
Shah, S.A., Potter, M.W., Ricciardi, R., Perugini, R.A. & Callery, M.P. (2001) FRAP-p70s6K signaling is required for pancreatic cancer cell proliferation. Journal of Surgical Research, 130, 123-130.
Sharom, F.J. (2008) ABC multidrug transporters : structure, function and role in chemoresistance. Pharmacogenomics, 9(1), 105-127.
Shin, W., Wu, A., Min, S., Shin, Y.C., Fleming, R.Y.D., Eckhardt, S.G. & Kim, H.J. (2020) iScience ll spatiotemporal gradient and instability of Wnt induce heterogeneous growth and differentiation of human intestinal organoids induce heterogeneous growth and differentiation of human intestinal organoids. ISCIENCE, 23(8), 101372.
Shukla, S.K., Purohit, V., Mehla, K., Cantley, L.C., Berim, L. & Singh, P.K. (2017) anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer article MUC1 and HIF-1alpha signaling crosstalk induces anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer. Cancer Cell, 71-87.
Skrypek, N., Duchêne, B., Hebbar, M., Leteurtre, E., Van Seuningen, I. & Jonckheere, N. (2013) The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family. Oncogene, 1714-1723.
Skrypek, N., Vasseur, R., Vincent, A., Duchêne, B., Seuningen, I.V. & Jonckheere, N. (2015) The oncogenic receptor ErbB2 modulates gemcitabine and irinotecan /SN-38 chemoresistance of human pancreatic cancer cells via hCNT1 transporter and multidrug-resistance associated protein MRP-2. Oncotarget, 6(13), 10853-10867.
Soledad, M., Varela, R., Mucci, S., Agustín, G., Richardson, V., Hanon, O.M., Furmento, V.A., Miriuka, S.G., Sevlever, G.E., Scassa, M.E. & Romorini, L. (2018) Regulation of cyclin E1 expression in human pluripotent stem cells and derived neural progeny. Cell Cycle, 17(14), 1719-1742.
Spitzwieser, M. (2016) Promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in human cancer cell lines, multidrug-resistant cell models and tumor, tumor-adjacent and tumor-distant tissues from breast cancer patients. Oncotarget, 7(45).
Sun, Q., Ye, Z., Qin, Yi, Fan, G., Ji, S., Zhuo, Q., Xu, W., Liu, W., Hu, Q., Liu, M., Zhang, Z., Xu, X. & Yu, X. (2020) Oncogenic function of TRIM2 in pancreatic cancer by activating ROS-related NRF2 /ITGB7 / FAK axis. Oncogene, 6572-6588.
Tadros, S., Shukla, S.K., King, R.J., Gunda, V., Vernucci, E., Abrego, J., Chaika, N.V., Yu, F., Lazenby, A.J., Berim, L., Grem, J., Sasson, A.R. & Singh, P.K. (2017) De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer. Cancer Research, 5503-5518.
Taira, N., Nihira, K., Yamaguchi, T., Miki, Y. & Yoshida, K. (2007) DYRK2 is targeted to the nucleus and controls p53 via Ser46 Phosphorylation in the apoptotic response to DNA damage. Molecular Cell, 25(5), 725-738.
Toledo, F. & Wahl, G.M. (2006) Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nature Reviews Cancer, 6(12), 909-915.
Toyoda, Y., Takada, T. & Suzuki, H. (2019) Inhibitors of human ABCG2: from technical background to recent updates with clinical implications. Front. Pharmacol, 10(MAR), 1-9.
Tsuboi, M., Taniuchi, K., Furihata, M., Naganuma, S., Kimura, M., Watanabe, R., Shimizu, T., Saito, M., Dabanaka, K., Hanazaki, K. & Saibara, T. (2016) Pancreatology Vav3 is linked to poor prognosis of pancreatic cancers and promotes the motility and invasiveness of pancreatic cancer cells. Pancreatology, 16(5), 905-916.
Turner, J.G., Gump, J.L., Zhang, C., Cook, J.M., Marchion, D., Hazlehurst, L., Munster, P., Schell, M.J., Dalton, W.S. & Sullivan, D.M. (2006). ABCG2 expression, function, and promoter methylation in human multiple myeloma. Blood, 108, 3881-3889.
Valenzuela, B., Nalda-Molina, R., Bretcha-Boix, P., Escudero-Ortíz, V., Duart, M.J., Carbonell, V., Sureda, M., Rebollo, J.P., Farré, J., Brugarolas, A. & Pérez-Ruixo, J.J. (2011) Pharmacokinetic and pharmacodynamic analysis of hyperthermic intraperitoneal oxaliplatin-induced neutropenia in subjects with peritoneal carcinomatosis. The Aaps Journal [Electronic Resource], 13(1), 72-82.
Vincent, A., Ducourouble, M. & Van Seuningen, I. (2008) Epigenetic regulation of the human mucin gene MUC4 in epithelial cancer cell lines involves both DNA methylation and histone modifications mediated by DNA methyltransferases and histone deacetylases. Faseb Journal, 22(8), 3035-3045.
Vincent, A., Herman, J., Schulick, R., Hruban, R.H. & Goggins, M. (2011) Pancreatic cancer: An overview. Lancet, 11(2), 168-180.
Xu, G., Kwon, G., Cruz, W.S., Marshall, C.A. & Mcdaniel, M.L. (2001) Metabolic regulation by leucine of translation initiation through the mTOR-signaling pathway by pancreatic cells. Diabetes, 50(2), 353-360.
Zhang, J., Deng, X. & Kahle, K.T. (2016) Leveraging unique structural characteristics of WNK kinases to achieve therapeutic inhibition. Science Signaling, 9(450), 1-4.
Zhou, C., Sun, H., Zheng, C., Gao, J., Fu, Q., Hu, N., Shao, X., Zhou, Y., Xiong, J., Nie, Ke, Zhou, H., Shen, L., Fang, H. & Lyu, J. (2018) Oncogenic HSP60 regulates mitochondrial oxidative phosphorylation to support Erk1/2 activation during pancreatic cancer cell growth. Cell Death & Disease, 9(2), 161.