Abstract
KRAS-driven and pancreatitis-associated pancreatic tumor initiation is dependent on EGFR.
Major finding: KRAS-driven and pancreatitis-associated pancreatic tumor initiation is dependent on EGFR.
Mechanism: EGFR signaling promotes cancer cell proliferation and acinar-to-ductal metaplasia.
Impact: Further studies on the clinical efficacy of EGFR inhibitors in pancreatic cancer are warranted.
Oncogenic KRAS and chronic pancreatic inflammation facilitate pancreatic tumor initiation in part via acinar-to-ductal metaplasia, which results in the conversion of acinar cells to progenitor-like ductal cells with increased transformation potential. However, although EGF receptor (EGFR) signaling induces metaplasia, EGFR inhibition has only shown limited therapeutic benefit in patients with pancreatic cancer. Using mouse models of pancreatic cancer driven by mutant Kras as well as human biopsies, Ardito and colleagues and Navas and colleagues detected upregulation of EGFR expression and activity in clusters of acinar cells prior to acinar-to-ductal metaplasia, acinar cells of damaged pancreata (pancreatitis), metaplastic areas, and pancreatic intraepithelial neoplasias (PanIN), suggesting that EGFR promotes pancreatic tumorigenesis. Consistent with this idea, both groups showed that Egfr deletion or treatment with erlotinib diminished PanIN formation and impaired progression to pancreatic ductal adenocarcinoma (PDAC). Furthermore, both studies demonstrated that ligand-mediated EGFR signaling was necessary to trigger metaplasia stimulated by mutant Kras or induction of pancreatitis. However, Tp53 loss was sufficient to bypass this requirement and to trigger EGFR-independent tumor growth. Downstream of EGFR, Ardito and colleagues showed that sustained ERK activation was required for metaplasia and the development of PanINs. In addition, Navas and colleagues identified elevated PI3K and STAT3 as critical downstream effectors in PDACs and showed that combined inhibition of these pathways abrogated cancer cell proliferation. Importantly, this dependence on EGFR was specific to pancreatic tumors, as Navas and colleagues showed that the growth of Kras-mutant lung and intestinal tumors was unaffected by Egfr loss. Taken together, these findings implicate EGFR activation as a critical and early event in KRAS-mutant pancreatic tumorigenesis and support additional testing of EGFR inhibitors in patients with pancreatic cancer.
