REFERENCES
2. Khalaf N, El-Serag HB, Abrams HR, Thrift AP. Burden of pancreatic cancer: from epidemiology to practice. Clin Gastroenterol Hepatol 2021;19:876-84.
3. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913-21.
5. Giovannetti E, van der Borden CL, Frampton AE, Ali A, Firuzi O, Peters GJ. Never let it go: stopping key mechanisms underlying metastasis to fight pancreatic cancer. Semin Cancer Biol 2017;44:43-59.
6. Tanaka M, Mihaljevic AL, Probst P, et al. Meta-analysis of recurrence pattern after resection for pancreatic cancer. Br J Surg 2019;106:1590-601.
7. Caparello C, Meijer LL, Garajova I, et al. FOLFIRINOX and translational studies: towards personalized therapy in pancreatic cancer. World J Gastroenterol 2016;22:6987-7005.
8. Singh RR, O'Reilly EM. New treatment strategies for metastatic pancreatic ductal adenocarcinoma. Drugs 2020;80:647-69.
9. El Hassouni B, Li Petri G, Liu DSK, et al. Pharmacogenetics of treatments for pancreatic cancer. Expert Opin Drug Metab Toxicol 2019;15:437-47.
10. Beatty GL, Werba G, Lyssiotis CA, Simeone DM. The biological underpinnings of therapeutic resistance in pancreatic cancer. Genes Dev 2021;35:940-62.
11. Sciarrillo R, Wojtuszkiewicz A, Assaraf YG, et al. The role of alternative splicing in cancer: from oncogenesis to drug resistance. Drug Resist Updat 2020;53:100728.
12. Alsafadi S, Houy A, Battistella A, et al. Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. Nat Commun 2016;7:10615.
13. Cai J, Damaraju VL, Groulx N, et al. Two distinct molecular mechanisms underlying cytarabine resistance in human leukemic cells. Cancer Res 2008;68:2349-57.
14. Wojtuszkiewicz A, Assaraf YG, Maas MJ, Kaspers GJ, Jansen G, Cloos J. Pre-mRNA splicing in cancer: the relevance in oncogenesis, treatment and drug resistance. Expert Opin Drug Metab Toxicol 2015;11:673-89.
15. Wang BD, Lee NH. Aberrant RNA splicing in cancer and drug resistance. Cancers (Basel) 2018;10:458.
16. Yoshida K, Ogawa S. Splicing factor mutations and cancer. Wiley Interdiscip Rev RNA 2014;5:445-59.
17. Effenberger KA, Urabe VK, Jurica MS. Modulating splicing with small molecular inhibitors of the spliceosome. Wiley Interdiscip Rev RNA 2017;8:10.1002/wrna.1381.
18. Zhang D, Meng F. A comprehensive overview of structure-activity relationships of small-molecule splicing modulators targeting SF3B1 as anticancer agents. ChemMedChem 2020;15:2098-120.
19. Eskens FA, Ramos FJ, Burger H, et al. Phase I pharmacokinetic and pharmacodynamic study of the first-in-class spliceosome inhibitor E7107 in patients with advanced solid tumors. Clin Cancer Res 2013;19:6296-304.
20. Gao Y, Koide K. Chemical perturbation of Mcl-1 pre-mRNA splicing to induce apoptosis in cancer cells. ACS Chem Biol 2013;8:895-900.
21. Xargay-Torrent S, López-Guerra M, Rosich L, et al. The splicing modulator sudemycin induces a specific antitumor response and cooperates with ibrutinib in chronic lymphocytic leukemia. Oncotarget 2015;6:22734-49.
22. Wan Y, Li Y, Yan C, Yan M, Tang Z. Indole: a privileged scaffold for the design of anti-cancer agents. Eur J Med Chem 2019;183:111691.
23. Dadashpour S, Emami S. Indole in the target-based design of anticancer agents: a versatile scaffold with diverse mechanisms. Eur J Med Chem 2018;150:9-29.
24. Parrino B, Schillaci D, Carnevale I, et al. Synthetic small molecules as anti-biofilm agents in the struggle against antibiotic resistance. Eur J Med Chem 2019;161:154-78.
25. Cascioferro S, Parrino B, Petri GL, et al. 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives as potent staphylococcal biofilm inhibitors. Eur J Med Chem 2019;167:200-10.
26. Parrino B, Carbone D, Cascioferro S, et al. 1,2,4-Oxadiazole topsentin analogs as staphylococcal biofilm inhibitors targeting the bacterial transpeptidase sortase A. Eur J Med Chem 2021;209:112892.
27. Carbone A, Cascioferro S, Parrino B, et al. Thiazole analogues of the marine alkaloid nortopsentin as inhibitors of bacterial biofilm formation. Molecules 2020;26:81.
28. Sivaprasad G, Perumal PT, Prabavathy VR, Mathivanan N. Synthesis and anti-microbial activity of pyrazolylbisindoles--promising anti-fungal compounds. Bioorg Med Chem Lett 2006;16:6302-5.
29. Leboho TC, Michael JP, van Otterlo WA, van Vuuren SF, de Koning CB. The synthesis of 2- and 3-aryl indoles and 1,3,4,5-tetrahydropyrano[4,3-b]indoles and their antibacterial and antifungal activity. Bioorg Med Chem Lett 2009;19:4948-51.
30. Li J, Ji J, Xu R, Li Z. Indole compounds with N-ethyl morpholine moieties as CB2 receptor agonists for anti-inflammatory management of pain: synthesis and biological evaluation. Medchemcomm 2019;10:1935-47.
31. Battaglia S, Boldrini E, Da Settimo F, et al. Indole amide derivatives: synthesis, structure-activity relationships and molecular modelling studies of a new series of histamine H1-receptor antagonists. Eur J Med Chem 1999;34:93-105.
32. Patel DV, Patel NR, Kanhed AM, et al. Further studies on triazinoindoles as potential novel multitarget-directed anti-Alzheimer's agents. ACS Chem Neurosci 2020;11:3557-74.
33. Toumi A, Boudriga S, Hamden K, et al. Synthesis, antidiabetic activity and molecular docking study of rhodanine-substitued spirooxindole pyrrolidine derivatives as novel α-amylase inhibitors. Bioorg Chem 2021;106:104507.
34. Xue S, Ma L, Gao R, Li Y, Li Z. Synthesis and antiviral activity of some novel indole-2-carboxylate derivatives. Acta Pharm Sin B 2014;4:313-21.
35. Carbone D, Parrino B, Cascioferro S, et al. 1,2,4-oxadiazole topsentin analogs with antiproliferative activity against pancreatic cancer cells, targeting GSK3β kinase. ChemMedChem 2021;16:537-54.
36. Cascioferro S, Attanzio A, Di Sarno V, et al. New 1,2,4-oxadiazole nortopsentin derivatives with cytotoxic activity. Mar Drugs 2019;17:35.
37. Li Petri G, Cascioferro S, El Hassouni B, et al. Biological evaluation of the antiproliferative and anti-migratory activity of a series of 3-(6-Phenylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1H-indole derivatives against pancreatic cancer cells. Anticancer Res 2019;39:3615-20.
38. Cascioferro S, Petri GL, Parrino B, et al. Imidazo[2,1-b] [1,3,4]thiadiazoles with antiproliferative activity against primary and gemcitabine-resistant pancreatic cancer cells. Eur J Med Chem 2020;189:112088.
39. Cascioferro S, Li Petri G, Parrino B, et al. 3-(6-Phenylimidazo [2,1-b][1,3,4]thiadiazol-2-yl)-1H-indole derivatives as new anticancer agents in the treatment of pancreatic ductal adenocarcinoma. Molecules 2020;25:329.
40. Li Petri G, Pecoraro C, Randazzo O, et al. New imidazo[2,1-b][1,3,4]thiadiazole derivatives inhibit FAK phosphorylation and potentiate the antiproliferative effects of gemcitabine through modulation of the human equilibrative nucleoside transporter-1 in peritoneal mesothelioma. Anticancer Res 2020;40:4913-9.
41. Randazzo O, Papini F, Mantini G, et al. "Open sesame?”: biomarker status of the human equilibrative nucleoside transporter-1 and molecular mechanisms influencing its expression and activity in the uptake and cytotoxicity of gemcitabine in pancreatic cancer. Cancers (Basel) 2020;12:3206.
42. Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 2013;27:221-34.
43. Greenwood JR, Calkins D, Sullivan AP, Shelley JC. Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution. J Comput Aided Mol Des 2010;24:591-604.
44. Protein data bank. Available from: https://pdb101.rcsb.org [Last accessed on 22 Sep 2021].
45. Olsson MHM, Søndergaard CR, Rostkowski M, Jensen JH. PROPKA3: consistent treatment of internal and surface residues in empirical pKa predictions. J Chem Theory Comput 2011;7:525-37.
46. Wolber G, Langer T. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J Chem Inf Model 2005;45:160-9.
47. Perricone U, Wieder M, Seidel T, Langer T, Padova A. The use of dynamic pharmacophore in computer-aided hit discovery: a case study. Methods Mol Biol 2018;1824:317-33.
48. Friesner RA, Murphy RB, Repasky MP, et al. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 2006;49:6177-96.
49. Carbone A, Parrino B, Di Vita G, et al. Synthesis and antiproliferative activity of thiazolyl-bis-pyrrolo[2,3-b]pyridines and indolyl-thiazolyl-pyrrolo[2,3-c]pyridines, nortopsentin analogues. Mar Drugs 2015;13:460-92.
50. Iwamura T, Katsuki T, Ide K. Establishment and characterization of a human pancreatic cancer cell line (SUIT-2) producing carcinoembryonic antigen and carbohydrate antigen 19-9. Jpn J Cancer Res 1987;78:54-62.
51. Owens RB, Smith HS, Nelson-Rees WA, Springer EL. Epithelial cell cultures from normal and cancerous human tissues. J Natl Cancer Inst 1976;56:843-9.
52. Meijer LL, Garajová I, Caparello C, et al. Plasma miR-181a-5p downregulation predicts response and improved survival after FOLFIRINOX in pancreatic ductal adenocarcinoma. Ann Surg 2020;271:1137-47.
53. Le Large TYS, Bijlsma MF, El Hassouni B, et al. Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma. J Exp Clin Cancer Res 2021;40:91.
54. Sciarrillo R, Wojtuszkiewicz A, El Hassouni B, et al. Splicing modulation as novel therapeutic strategy against diffuse malignant peritoneal mesothelioma. EBioMedicine 2019;39:215-25.
55. Sciarrillo R, Wojtuszkiewicz A, Kooi IE, et al. Using RNA-sequencing to detect novel splice variants related to drug resistance in in vitro cancer models. J Vis Exp 2016;54714.
56. Cretu C, Agrawal AA, Cook A, et al. Structural basis of splicing modulation by antitumor macrolide compounds. Mol Cell 2018;70:265-73.e8.
57. Finci LI, Zhang X, Huang X, et al. The cryo-EM structure of the SF3b spliceosome complex bound to a splicing modulator reveals a pre-mRNA substrate competitive mechanism of action. Genes Dev 2018;32:309-20.
58. Maguire SL, Leonidou A, Wai P, et al. SF3B1 mutations constitute a novel therapeutic target in breast cancer. J Pathol 2015;235:571-80.
59. Biankin AV, Waddell N, Kassahn KS, et al. Australian Pancreatic Cancer Genome Initiative. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012;491:399-405.
60. Dvinge H, Kim E, Abdel-Wahab O, Bradley RK. RNA splicing factors as oncoproteins and tumour suppressors. Nat Rev Cancer 2016;16:413-30.
61. Shiraishi Y, Chiba K, Okada A. SF3B1ness score: screening SF3B1 mutation status from over 60,000 transcriptomes based on a machine learning approach. bioRxiv 2019; doi: 10.1101/572834.
62. Seiler M, Peng S, Agrawal AA, et al. Cancer Genome Atlas Research Network. Somatic mutational landscape of splicing factor genes and their functional consequences across 33 cancer types. Cell Rep 2018;23:282-96.e4.
63. Darman RB, Seiler M, Agrawal AA, et al. Cancer-associated SF3B1 hotspot mutations induce cryptic 3' splice site selection through use of a different branch point. Cell Rep 2015;13:1033-45.
64. Logan-Collins J, Thomas RM, Yu P, et al. Silencing of RON receptor signaling promotes apoptosis and gemcitabine sensitivity in pancreatic cancers. Cancer Res 2010;70:1130-40.
65. Chakedis J, French R, Babicky M, et al. Characterization of RON protein isoforms in pancreatic cancer: implications for biology and therapeutics. Oncotarget 2016;7:45959-75.
66. Chakedis J, French R, Babicky M, et al. A novel protein isoform of the RON tyrosine kinase receptor transforms human pancreatic duct epithelial cells. Oncogene 2016;35:3249-59.
67. Ciccolini J, Serdjebi C, Peters GJ, Giovannetti E. Pharmacokinetics and pharmacogenetics of Gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective. Cancer Chemother Pharmacol 2016;78:1-12.
68. Buxade M, Parra-Palau JL, Proud CG. The Mnks: MAP kinase-interacting kinases (MAP kinase signal-integrating kinases). Front Biosci 2008;13:5359-73.
69. Scheper GC, Parra JL, Wilson M, et al. The N and C termini of the splice variants of the human mitogen-activated protein kinase-interacting kinase Mnk2 determine activity and localization. Mol Cell Biol 2003;23:5692-705.
70. Calabretta S, Bielli P, Passacantilli I, et al. Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells. Oncogene 2016;35:2031-9.
71. Jaramillo AC, Hubeek I, Broekhuizen R, et al. Expression of the nucleoside transporters hENT1 (SLC29) and hCNT1 (SLC28) in pediatric acute myeloid leukemia. Nucleosides Nucleotides Nucleic Acids 2020;39:1379-88.
72. Hubeek I, Giovannetti E, Broekhuizen AJ, Pastor-Anglada M, Kaspers GJ, Peters GJ. Immunocytochemical detection of hENT1 and hCNT1 in normal tissues, lung cancer cell lines, and NSCLC patient samples. Nucleosides Nucleotides Nucleic Acids 2008;27:787-93.
73. Lee SC, Dvinge H, Kim E, et al. Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins. Nat Med 2016;22:672-8.
74. Salton M, Misteli T. Small molecule modulators of Pre-mRNA splicing in cancer therapy. Trends Mol Med 2016;22:28-37.
76. Jyotsana N, Heuser M. Exploiting differential RNA splicing patterns: a potential new group of therapeutic targets in cancer. Expert Opin Ther Targets 2018;22:107-21.
77. Giovannetti E, Del Tacca M, Mey V, et al. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res 2006;66:3928-35.
78. Myers SN, Goyal RK, Roy JD, Fairfull LD, Wilson JW, Ferrell RE. Functional single nucleotide polymorphism haplotypes in the human equilibrative nucleoside transporter 1. Pharmacogenet Genomics 2006;16:315-20.
79. Supadmanaba IGP, Mantini G, Randazzo O, et al. Interrelationship between miRNA and splicing factors in pancreatic ductal adenocarcinoma. Epigenetics 2021;1-21.
80. Sankar S, Guillen-Navarro M, Ponthan F, et al. The SF3b splicing complex regulates DNA damage response in acute lymphoblastic leukemia. Blood 2019;134:1237.
81. Firuzi O, Che PP, El Hassouni B, et al. Role of c-MET Inhibitors in overcoming drug resistance in spheroid models of primary human pancreatic cancer and stellate cells. Cancers (Basel) 2019;11:638.
82. Hu CY, Xu XM, Hong B, et al. Aberrant RON and MET co-overexpression as novel prognostic biomarkers of shortened patient survival and therapeutic targets of tyrosine kinase inhibitors in pancreatic cancer. Front Oncol 2019;9:1377.
