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. While several EGFR inhibitors have been approved, within a short period of time, the majority of patients develop mutations in the EGFR kinase domain, which is the drug binding site, and stop responding to the treatment.
To address this significant unmet need, investigational DGD1202, which targets mutant EGFR in a manner other than inhibition of EGFR tyrosine kinase activity, is being evaluated. The compound has been designed to inhibit dimerization of EGFR and induce 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 models.
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