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 successful been developed and marketed, however, 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.
Ray et al. Inducing Oncoprotein Degradation to Improve Targeted Cancer Therapy. Neoplasia. 2015 Sep;17(9):697-703 https://www.ncbi.nlm.nih.gov/pubmed/26476077
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
Ahsan et al. Destabilization of the epidermal growth factor receptor (EGFR) by a peptide that inhibits EGFR binding to heat shock protein 90 and receptor dimerization. J Biol Chem. 2013 Sep 13;288(37):26879-86 https://www.ncbi.nlm.nih.gov/pubmed/23897823