Pancreatic ductal adenocarcinoma (PDAC) represents the fourth cause of cancer-associated death in the West. This type of cancer has a very poor prognosis notably due to the development of chemoresistance when treatments including gemcitabine and Abraxane (Nab-paclitaxel) were prescribed. The identification of new treatment circumventing this chemoresistance represents a key challenge. Previous studies demonstrated that the activation of orexin receptor type 1 (OX1R), which was ectopically expressed in PDAC, by its natural ligand named orexin-A (OxA), led to anti-tumoral effect resulting in the activation of mitochondrial pro-apoptotic mechanism. Here, we demonstrated that OxA inhibited the pancreatic cancer cell (AsPC-1) growth and inhibited the tumor volume in preclinical models as effectively as gemcitabine and Nab-paclitaxel. Moreover, the combination therapy including OxA plus gemcitabine or OxA plus Nab-paclitaxel was additive on the inhibition of cancer cell growth and tumor development. More importantly, the treatment by OxA of chemoresistant tumors to gemcitabine or Nab-paclitaxel obtained by successive xenografts in mice revealed that OxA was able to induce a strong inhibition of tumor development, whereas no OxA resistance was identified in tumors. The OX1R/OxA system might be an innovative and powerful alternative treatment of chemoresistant PDAC.

Preclinical study and histological analysis of anti-tumoral effect of OxA and Nab-paclitaxel. (A) Impact of three injections/week of 100 µg OxA, 230 µg Nab-paclitaxel, or 100 µg OxA plus 230 µg Nab-paclitaxel on volume of tumors developed from subcutaneously xenografted ASPC-1 cells in nude mice. The tumor development was measured with a caliper. (B) Determination of OX1R expression and caspase-3 activation by histologic immunostaining in xenografted AsPC-1 resected tumors from mice treated with PBS (control), OxA (OxA), Nab-paclitaxel (pacli), or OxA plus Nab-paclitaxel (OxA + pacli). Magnification was 40× (OX1R expression) and 20× (caspase-3 activation). Data were the means ± SEM of six tumors in each group. *p<0.05.