Combination of niclosamide and erlotinib to treat lung, head, and neck cancers as well as overcome resistance to alternative treatments.
- Anti-cancer treatment combines two existing and approved therapeutics.
- Effective cancer treatment for erlotinib resistant patients.
Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective anti-cancer agents, a recent emergence of resistance to these therapies is a major clinical problem. The majority of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) show an initial response to these inhibitors but after approximately a year, resistance develops and efficacy decreases significantly.
EGFR tyrosine kinase inhibitors such as erlotinib and gefitinib, are effective treatments for NSCLC; however these therapies lose efficacy over time. Emory researchers have found that erlotinib enhances phosphorylation of STAT3, a transcription factor that mediates the expression of a variety of genes in response to cell stimuli and plays a role in cell growth and apoptosis. This STAT3 phosphorylation increases STAT3 activation which leads to elevated levels of Bcl2/Bcl-XL, a survival signal linked to cancer, at both the mRNA and protein level, and the consequent loss of erlotinib sensitivity. To address this sensitivity loss, a potent STAT3 inhibitor, niclosamide, can be used in combination with erlotinib to block STAT3 phosphorylation and the resulting transcriptional activity. In this way, niclosamide would block erlotinib-induced activation of the STAT3/Bcl2/Bcl-XL survival pathway in lung cancer cells and lead to the reversal of erlotinib resistance in vitro and in vivo.
- In vitro treatment of cells with niclosamide blocks erlotinib-induced activation of STAT3/Bcl2/Bcl-XL and reverses erlotinib resistance.
- Combination treatment of erlotinib and niclosamide overcomes acquired erlotinib resistance in vivo in a xenograft mouse model of cancer.