Journal
FRONTIERS IN ONCOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2022.904327
Keywords
GPCR; pancreatic cancer; orexins; chemoresistance; apoptosis
Categories
Funding
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Universite de Paris
- Institut National du Cancer (INCA) (PAIR Pancreas) [PAN18-045]
- Ligue Contre le Cancer [R16020HH, GB/MA/CD/EP-12062]
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Orexin-A can effectively inhibit the growth of pancreatic cancer cells and significantly reduce tumor volume in preclinical models. Combination therapy with Orexin-A plus gemcitabine or Orexin-A plus Nab-paclitaxel shows additive effects in inhibiting cancer cell growth and tumor development.
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.
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