Understanding EGFR Signaling Networks May Lead to New Cancer Treatments

Cancer researchers have shown that a combination of drugs already approved by the [US] Food and Drug Administration (FDA) could block the oncogenic activity of EGFR (epidermal growth factor receptor) and restore drug sensitivity in advanced cases of metastatic lung adenocarcinoma.

EGFR activation is both a key molecular driver of cancer progression and the target of a broad class of molecular agents designed to treat advanced forms of the disease. Nevertheless, drug resistance develops through several mechanisms, including activation of AKT signaling. AKT, also known as protein kinase B (PKB), is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.

Investigators at Case Western Reserve University (Cleveland, OH, USA) and colleagues at Mount Sinai School of Medicine (New York, NY, USA) characterized the downstream mediators of EGFR signaling in order to develop new classes of targeted molecular therapies to treat resistant forms of cancer.

They reported in the June 1, 2012, online edition of the Journal of Clinical Investigation that they had identified a transcriptional network involving the tumor suppressor proteins Krüppel-like factor 6 (KLF6) and forkhead box O1 (FOXO1). KLF6 and FOXO1 are tumor suppressor genes that are turned off in actively growing cancer cells.

Working with both cell culture and xenograft models of lung adenocarcinoma, the investigators showed that the use of the FDA-approved drug trifluoperazine hydrochloride (a medication used to treat schizophrenia), which had been shown to inhibit FOXO1 nuclear export, restored sensitivity to AKT-driven erlotinib (a targeted cancer drug) resistance through modulation of the KLF6/FOXO1 signaling cascade.

“Because of the financial constraints and length of time it takes to bring new drugs through clinical trials, scientists are moving toward using existing drugs in new ways so that the process of translating the discoveries of today into the treatments of tomorrow can be accelerated,” said senior author Dr. Goutham Narla, assistant professor of medicine at Case Western Reserve University.

Results of this study highlight the central importance of defining key signaling networks in cancer and the potential use of this information to identify clinically relevant modulators of treatment response.

Related Links:
Case Western Reserve University
Mount Sinai School of Medicine