Ligandos autocrinos en la resistencia a erlotinib del cáncer pancreático
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Pancreatic adenocarcinoma is one of the solid tumors with poorest prognosis. Its growing
incidence projects it to be the second cause of cancer-related deaths after 2030. Self-sufficiency
of growth factors and deregulation of ErbB receptors signaling pathways have been shown to
play a fundamental role in its etiology. One of the mechanisms used by the tumor cell for the
aberrant activation of this family of receptors is the autocrine secretion of EGF-related ligands.
In the last years, therapies targeting ErbB receptors have emerged, but they have shown limited
efficacy in pancreatic cancer. The overexpression of ErbB receptors and their ligands has
demonstrated a critical participation in acquired resistance to these therapies.
In the present study, we aimed to evaluate the contribution of this phenomenon to the
tumorigenesis of pancreatic cancer and insensitivity to EGFR inhibitors. To this end, we used
four pancreatic cancer cell lines (AsPc-1, BxPc3, Capan-1 and HPAF-II) and evaluated its
sensitivity to EGFR inhibitor erlotinib, an FDA-approved drug for the treatment of pancreatic
adenocarcinomas in combination with gemcitabine. We determined the expression of ErbB
receptors shown by each cell line and chose two of them (BxPc-3 and HPAF-II) to analyze by RTPCR
the gene expression of three EGF-related ligands (NRG-1, EPRR and TFG-α), prior and after
treatment with erlotinib.
EGFR inhibition rapidly produced an enhanced expression of EPR and TGF-α ligands in BxPc3,
while HPAF-II downregulated both growth factors. Taken together, our findings demonstrate
that treatment with erlotinib induces a change in gene expression of pancreatic cancer cell lines,
which confers them a previously unrecognized mechanism of acquired resistance, allowing them
to evade the cytostatic effects of this drug