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[10]
is linked with resistance to chemotherapeutic drugs . Similarly, TP53 mutations of pancreatic cancer were
[11]
associated with higher resistance to chemotherapy with gemcitabine . Extensive research in the field,
however, has supported that additional intracellular mechanisms and tumor microenvironment are equally
[12]
important factors that reduce the efficacy of chemotherapy in pancreatic malignancies . Altered expression
of key enzymes involved in critical metabolic cellular pathways, such as aerobic glycolysis and glutamine
[13]
metabolism, appears to induce a chemoresistant phenotype in pancreatic cancer cells . Moreover,
epigenetic mechanisms and especially target of methylation induced silencing 1 (TMS1) methylation are
[14]
involved in acquired chemoresistance . As far as the tumor microenvironment is concerned, PDAC is
characterized by a dense extracellular matrix and fibroblastic stroma, which leads to decreased
bioavailability of drugs in the tumor and, subsequently, diminished efficacy of the various chemotherapy
[15]
regimens . Pancreatic stellate cells and cancer-associated fibroblasts contribute to this chemoresistant
phenotype through various mechanisms, including the production of components of the tumor stroma and
the prevention of H O -induced apoptosis . Finally, a study by Amit et al. demonstrated the inactivation of
[12]
2
2
gemcitabine by tumor-associated macrophages, implying the potential role of the innate immune system in
[16]
chemoresistance .
Drug-specific resistance pathways may also be active in PDAC. Gemcitabine is one of the most used drugs -
in combination with nab-paclitaxel - and as a deoxycytidine analog, it interferes with DNA synthesis.
Suppression of the nucleoside transporter hENT1 gene or alterations of the function of deoxycytidine kinase
[17]
and ribonucleoside reductase contribute to the resistance of pancreatic cancer cells to gemcitabine .
Overexpression of the dihydropyrimidine dehydrogenase and thymidylate synthase is involved in the
resistance to gemcitabine and 5-FU . Irinotecan is also a major drug for PDAC, used in the FOLFIRINOX
[18]
[5-FU/leucovorin/irinotecan/oxaliplatin (FFX)] regimen. The activity of carboxyl-esterase-2 (CES2) in
cancer cells is essential for the transformation of irinotecan to the SN-38 active derivative, and low
expression of CES2 has been associated with poor prognosis in BR-PDAC . Furthermore, DNA repair
[19]
enzymes define the resistance of pancreatic cancer cells to platinum compounds and radiation; the excision
repair cross-complementing proteins (ERCC) 1, 2, and 4 render cancer cells resistant to platinum agents,
although a recent study failed to show any association between these enzymes and response to FFX
[20]
chemotherapy . Common resistance mechanisms to paclitaxel chemotherapy include taxane-metabolizing
enzyme activity (e.g., CYP1 enzymes), overexpression of multidrug resistance proteins regulating the efflux
of taxanes, tubulin gene mutations, and signaling molecules (POLO kinase, Bcl-2, and the ACT pathway) .
[21]
Radioresistance is another impediment to the effective treatment of this extremely aggressive malignancy.
PDAC is characterized by diffuse hypoxia throughout the tumor and its microenvironment ; thus,
[22]
radiotherapy’s efficacy is quite limited. Moreover, pancreatic stellate cells, as mentioned above, inhibit H O 2
2
-induced apoptosis, one of the main mechanisms through which radiotherapy elicits its cytotoxic
[23]
properties . Finally, cancer stem cells have been associated with increased radioresistance due to their
enhanced ability of DNA repair and slow proliferation .
[24]
NEOADJUVANT CHEMOTHERAPY FOR PDAC
Monotherapy and older chemotherapy regimens for LA-PDAC
LA-PDAC of the pancreatic head and body/tail is defined by tumor contact of more than 180° with the
superior mesenteric artery (SMA) or celiac axis (CA). Body/tails tumors involving the aorta are also deemed
inoperable. Finally, the inability to reconstruct the superior mesenteric vein (SMV) or portal vein (PV) due
to tumor invasion or thrombus occlusion characterizes LA-PDAC .
[6]