Therapeutic options for the management of pancreatic cancer

Table 1 Cellular mechanisms of therapeutic resistance in pancreatic cancer

Cellular pathways	Mutated gene	Ref.
Cell-cycle control	CDK2NA (90%); APC2	Almoguera et al[54]; Schutte et al[71];Hahn et al[72]
RAS	KRAS (90%); MAP2K4	Almoguera et al[54]; Hruban et al[56];Pellegata et al[57];Hezel et al[58];Maitra et al[59]
DNA damage repair	TP53 (75%-90%)	Almoguera et al[54];Redston et al[67];Olive et al[68]
TGF-β	DPC4 (50%), SMAD4	Almoguera et al[54];Yachida et al[73]
Apoptosis	CASP10; CAD	Jones et al[77]
Cell adhesion	FAT; PCDH9	Jones et al[77]
Hedgehog	GLI1; GLI3	Jones et al[77]
Integrin	ILK; LAMA1	Jones et al[77]
JNK	MAP4K3; TNF	Jones et al[77]
Small GTPases	PLCB3; RP1	Jones et al[77]
Wnt-β-catenin	MYC; TSC2	Jones et al[77]

APC: Adenomatous polyposis coli; CDK2NA: Cyclin-dependent kinase inhibitor 2 A; CAD: Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase; CASP10: Caspase 10; DPC4: deleted in pancreatic cancer, locus 4; FAT: Fat tumor suppressor; GLI 1: Glioma-associated oncogene; GLI3: Glioma-associated oncogene 3; GTPases: Guanosine triphosphate; Wnt-B-catenin: Wingless type B-catenin; ILK: Integrin-linked kinase; JNK: c-Jun N-ternmial kinases; KRAS: Kristen rat sarcoma; LAMA1: Laminin A-1 chain; MAP2K4: Mitogen-activated protein kinase kinase 4; MAP4K3: Mitogen-activated protein-3 kinase-3: TNF: Tumor necrosis factor; MYC: Myelocytomatosis oncogene; PCDH9: Procadherin 9; PLCB3: Phospholipase C, beta 3; RP1: Retinitis pigementosa 1; SMAD4: Mothers against decapentaplegic homolog 4; TGF-β: Transforming growth factor β; TP53: Tumor protein 53; TSC2: Tuberous sclerosis 2; RAS: Rat sarcoma.

Table 2 Extracellular mechanisms of thereapeutic resistance in pancreatic cancer

Potential therapeutic targets	Extracellular response	Ref.
K-ras mutant oncogene	Proliferation of desmoplastic reaction (leukocytes, fibroblasts, endothelial cells, neuronal cells, collagen, hyaluron): upregulation of GM-CSF	Chu 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 fibroblasts	Bailey 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 cells	Evasion of the immune system	Bayne et al[87]; Pylayeva-Gupta et al[88]
Desmoplastic reaction	Anti-angiogenesis; hypoxic tumor environment	Komar et al[86]

K-ras: Kinase-rat sarcoma; GM-CSF: Granulocyte macrophage colon-stimulating factor.

Table 3 Therapies for the management of pancreatic cancer

Therapeutic option	Subset	Ref.
Surgical resection	Cephalic pancreatoduodenectomy Distal pancreatectomy Total pancreatectomy	Hidalgo[41]
Chemotherapy	Neoadjuvant Gemcitabine Adjuvant Gemcitabine 5-Fluorouracil Advanced disease Gemcitabine Gemcitabine + fluropyrimidines Gemcitabine + platinum analogs Gemcitabine + erlotinib FOLFIRINOX Nab-paclitaxel	Lemmens 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 therapy	Neoadjuvant 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 radiotherapy	Pisters 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 therapy	Target specific point mutations Mitomycin C Immune system stimulation	Jones et al[77]; Villarroel et al[153]; Yanagimoto et al[154]