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Copyright ©2014 Baishideng Publishing Group Inc.
World J Gastroenterol. Aug 28, 2014; 20(32): 11142-11159
Published online Aug 28, 2014. doi: 10.3748/wjg.v20.i32.11142
Table 1 Cellular mechanisms of therapeutic resistance in pancreatic cancer
Cellular pathwaysMutated geneRef.
Cell-cycle controlCDK2NA (90%); APC2Almoguera et al[54]; Schutte et al[71];Hahn et al[72]
RASKRAS (90%); MAP2K4Almoguera et al[54]; Hruban et al[56];Pellegata et al[57];Hezel et al[58];Maitra et al[59]
DNA damage repairTP53 (75%-90%)Almoguera et al[54];Redston et al[67];Olive et al[68]
TGF-βDPC4 (50%), SMAD4Almoguera et al[54];Yachida et al[73]
ApoptosisCASP10; CADJones et al[77]
Cell adhesionFAT; PCDH9Jones et al[77]
HedgehogGLI1; GLI3Jones et al[77]
IntegrinILK; LAMA1Jones et al[77]
JNKMAP4K3; TNFJones et al[77]
Small GTPasesPLCB3; RP1Jones et al[77]
Wnt-β-cateninMYC; TSC2Jones et al[77]
Table 2 Extracellular mechanisms of thereapeutic resistance in pancreatic cancer
Potential therapeutic targetsExtracellular responseRef.
K-ras mutant oncogeneProliferation of desmoplastic reaction (leukocytes, fibroblasts, endothelial cells, neuronal cells, collagen, hyaluron): upregulation of GM-CSFChu et al[78]; Neesse et al[79]; Ying et al[81]; Nolan-Stevaux et al[82]; Bayne et al[87]
Sonic hedgehog (SHH)Growth and differenatiation of stromal fibroblastsBailey et al[83]; Tian et al[84]; Olive et al[85]
Tumor associated macrophages (TAMs); cancer associated fibroblasts (CAFs); regulatory T-cells (Treg); myeloid derived suppressor cellsEvasion of the immune systemBayne et al[87]; Pylayeva-Gupta et al[88]
Desmoplastic reactionAnti-angiogenesis; hypoxic tumor environmentKomar et al[86]
Table 3 Therapies for the management of pancreatic cancer
Therapeutic optionSubsetRef.
Surgical resectionCephalic pancreatoduodenectomy Distal pancreatectomy Total pancreatectomyHidalgo[41]
ChemotherapyNeoadjuvant Gemcitabine Adjuvant Gemcitabine 5-Fluorouracil Advanced disease Gemcitabine Gemcitabine + fluropyrimidines Gemcitabine + platinum analogs Gemcitabine + erlotinib FOLFIRINOX Nab-paclitaxelLemmens et al[101]; Gillen et al[102]; Neoptolemos et al[108]; Burris et al[118]; Heinemann et al[119]; Reni et al[120]; Moore et al[122]; Neesse et al[79]
Radiation therapyNeoadjuvant Radiation + 5-fluorouracil Radiation + paclitaxel Proton beam radiation + capecitabine Adjuvant Radiation + 5-Fluorouracil Radiation + gemcitabine Radiation + chemotherapy Advanced Radiation + 5-fluorouracil Radiation + chemotherapy Stereotactic body radiotherapyPisters et al[131]; Hong et al[133]; Yeo et al[140]; Regine et al[138]; Neoptolemos et al[137]; Moertel et al[144]; Schellenberg et al[147]
Personalized therapyTarget specific point mutations Mitomycin C Immune system stimulationJones et al[77]; Villarroel et al[153]; Yanagimoto et al[154]