HER2 and ESR1 mutations as examples of novel druggable targets
The utility of detailed preclinical work on potentially druggable genes is nicely illustrated by the study of HER2 mutations in breast cancer. Data from eight breast cancer genome-sequencing studies identified 25 patients with HER2 somatic mutations without HER2 amplification. Thirteen HER2 mutations were functionally characterized by using in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments. The results showed that the investigational drug neratinib, an irreversible HER2 inhibitor, rather than lapatinib, an approved HER2 kinase inhibitor, was a better approach for clinical studies since some of the recurrent mutations were naturally lapatinib-resistant. This is a result that simple drug somatic mutation matching software would not have revealed. Currently, patients with advanced HER2 mutation-positive tumors are being enrolled into a single-agent study of neratinib (NCT01670877). Point mutations in the estradiol-binding domain of the estrogen receptor gene (ESR1) are emerging as a potent cause of acquired endocrine therapy resistance. Although there are no drugs that specifically target these mutations, alternative endocrine therapies may be effective in this setting and this possibility will soon be addressed in clinical trials.