Targeting EGFR in Pancreatic Cancer Treatment

Abstract

The prognosis of patients with pancreatic cancer is extremely poor, and current systemic therapies provide marginal survival benefits for treated patients. The era of targeted therapies has offered a new avenue to search for potentially more effective strategies. Epidermal growth factor receptor (EGFR) is a member of the erbB/human epidermal growth factor receptor family of tyrosine kinases, which includes erbB2/HER2, erbB3/HER3 and erbB4/HER4. Epidermal growth factor receptor overexpression may be detected in up to 90% of pancreatic tumors. Two pharmacologic approaches have been successfully used to inhibit epidermal growth factor receptor function in cancer treatment: neutralizing monoclonal antibodies and small molecule tyrosine inhibitors. The randomized trials studying the addition of EGFR targeted agents to gemcitabine compared with gemcitabine alone have been disappointing, although results with the EGFR tyrosine kinase inhibitor erlotinib were statistically significant but clinically of marginal benefit. In this article, we review the epidermal growth factor receptor signaling network in pancreatic cancer, the strategies to increase the effectiveness of epidermal growth factor receptor inhibitors, and the clinical trials of these inhibitors in pancreatic cancer.

The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways

“…This was important to establish, as EGFR is a key regulator of numerous oncogenic downstream signaling pathways (31,43) that were previously found to be inhibited by NDRG1 (4,6,8,(17)(18)(19). Considering the differences between tumors regarding their genetic background, all studies were conducted with both cell lines, to gain insight into NDRG1 function and gauge common functions between cell types.…”

“…Erlotinib-Currently, EGFR inhibitors are widely used clinically for the treatment of a variety of cancers (28,31,70). However, this class of drugs has significant limitations due to the following: 1) the development of resistance in some cancers, and 2) the numerous mutations of EGFR in individual cancers that render these agents ineffective (28,31,70).…”

“…However, this class of drugs has significant limitations due to the following: 1) the development of resistance in some cancers, and 2) the numerous mutations of EGFR in individual cancers that render these agents ineffective (28,31,70). Hence, a novel strategy to inhibit this important oncogene is essential.…”

Expression Patterns of Growth and Survival Genes with Prognostic Implications in Advanced Pancreatic Cancer

“…The epidermal growth factor receptor (EGFR) pathway has a major importance in pancreatic cancer (1). Erlotinib, a tyrosine kinase inhibitor (TKI) of EGFR, was tested in combination with gemcitabine as first-line treatment in a randomized trial of patients with advanced pancreatic cancer (2).…”

“…Increased AKT pathway activity has been found in up to 60% of pancreatic cancer tissues and cell lines. Murine leukemia viral oncogene (RAF)-mitogen-activated protein kinase (MAPK) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-AKT pathway activation lead to up-regulation of cyclin D1 (CCND1) and avian myelomatosis viral oncogene homolog (MYC) transcription and activity and to stimulation of the nuclear factor kappa B subunit (NFĸB) pathway (1,10,11). MYC overexpression is extremely common in pancreatic cancer tissues, while low amplification occurs in approximately 30% of cases (12).…”