EGFR Signaling Mediates KRAS Involvement in Mouse Models of Pancreatic Carcinogenesis

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(ChemotherapyAdvisor) – Epidermal growth factor receptor (EGFR) signaling plays a key role in pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDA) tumorigenesis and progression, suggesting a new potential therapeutic target, found a pair of preclinical papers published in Cancer Cell.

Pancreatic inflammation causes duct-like cells to replace acini – so-called “acinar-to-ductal” metaplasia (ADM). KRAS mutations appear to be a risk factor for pancreatic cancer partly because they disrupt the normal post-inflammation reversion of ADM metaplasic cells back to acini cell populations, “creating a reservoir of cells susceptible to additional oncogenic changes,” giving rise to Pan IN lesions (precursors to PDA), noted Rushika M. Perera, PhD, and Nabeel Bardeesy, PhD, both of the Massachusetts General Hospital in Boston and Harvard Medical School, in an accompanying essay.

But the two new studies show that EGFR deletion delays PDA tumorigenesis in KRAS-TP53 mutant mouse models -- and one of the studies found that EGFR knockout completely prevents KRAS mutation-mediated PDA tumorigenesis, reported lead author Carolina Navas, PhD, of the Molecular Oncology Program at the National Center of Oncobiology Research in Madrid, Spain, and coauthors.

EGFR inhibition “effectively eliminates KRAS-driven tumorigenesis in vivo,” noted the other study's lead author, Christine Ardito, PhD, of the Department of Pharmacological Sciences at Stony Brook University in New York, and colleagues.

“Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation, Dr. Ardito and her coauthors wrote.

Together, the new studies “establish that EGFR is required for both the initiation and survival of ADM (and PanIN) lesions and show that its ablation restricts the development of PDA,” noted Rushika M. Perera, PhD, and Nabeel Bardeesy, PhD, both of the Massachusetts General Hospital in Boston and Harvard Medical School, in an accompanying essay.

Both teams “found that EGFR expression is up-regulated in ADM and PanIN lesions in these models and in human pancreatitis specimens,” Perera and Bardseey wrote.

Erlotinib and gemcitabine offer modest benefits to PDA patients, suggesting EGFR signaling is less important in more advanced PDA – and suggesting a way forward for drug development, Perera and Bardseey noted: the new studies “support the potential of targeting TGFa-ADAM17-EGFR axis as an approach to PDA prevention.”            

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