Mutations that lead to EGFR overexpression (known as upregulation or amplification) have been associated with a number of cancers. These mutations lead to constant activation of EGFR, which produces uncontrolled cell division. Several EGFR inhibitors have been successfully developed and marketed, however, within a short period of time, a majority of patients develop mutations in the EGFR kinase domain, which is the drug binding site, and are no longer responding to the treatment.
To successfully treat these patients, a cancer therapeutic, DGD1202, that targets mutant EGFR in a manner other than inhibition of EGFR tyrosine kinase activity is being developed. The compound inhibits dimerization of EGFR and induces degradation of the receptor, rather than simply inhibiting its activity. This mechanism of action has been shown preclinically to specifically target cancer cells with EGFR mutations, leading to a profound reduction in tumor volume in models of lung cancer resistant to current therapies, as well as head and neck cancer.
About 15% of non-small cell lung cancers (314,000 new patients/year/worldwide) contain mutations within the EGFR kinase domain. While inhibition of EGFR tyrosine kinase (TKI) activity is effective for some patients, within 9 to 15 months of treatment, 100% of patients acquire resistance. The need for effective treatment strategies in this population is critical.
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Ahsan et al. Efficacy of an EGFR-specific peptide against EGFR-dependent cancer cell lines and tumor xenografts. Neoplasia. 2014 Feb;16(2):105-14. https://www.ncbi.nlm.nih.gov/pubmed/24709418
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