Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are detected in 10-15% of Caucasian and 30-40% of Asian patients with non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib and afatinib, are the standard of care initial treatment for patients with advanced EGFR mutant lung cancer. Although the vast majority of patients have significant tumor reductions with EGFR inhibitor treatment, acquired drug resistance inevitably develops in the majority of patients. For the most common mechanism of acquired resistance, EGFR T790M, detected in 60% of patients, osimertinib (AZD9291), a chemically diverse (pyrimidine; gefitinib, erlotinib and afatinib are quinazolines) mutant selective covalent EGFR inhibitor, is clinically effective in >60% of patients and has recently been approved for clinical use in the United States, Europe and Japan. However, resistance mechanisms to mutant selective EGFR inhibitors have already begun to be identified both in preclinical models and from patients. These include EGFR C797S, the site of covalent binding of osimertinib, which we identified by sequencing of plasma DNA from patients who relapsed on osimertinib treatment. Remarkably, EGFR mutations that cause resistance to osimertinib retain sensitivity to quinazoline based EGFR inhibitors including gefitinib when present in the absence of EGFR T790M. In contrast cancers with three EGFR mutations (EGFR activating mutation, EGFR T790M and EGFR C797S) are resistant to all current EGFR inhibitors. In collaboration with Michael Eck (Core B; structure), we have recently identified and studied a novel mutant selective allosteric EGFR inhibitor (EAI045). In conjunction with cetuximab EAI045 is effective both in vitro and in vivo in EGFR mutant models harboring C797S suggesting that novel drug development approaches can identify unique strategies to inhibiting mutant EGFR even in the presence of multiple drug resistance mutations to EGFR TKIs. The current clinical paradigm is to treat EGFR mutant lung cancer patients with successive single agent EGFR TKIs. Our recent preclinical studies, however, demonstrate that osimeritinib and gefitinib can overcome non- overlapping EGFR mediated drug resistance mutations, suggesting that dual EGFR inhibition with both agents may be a more effective strategy. In the current proposal we will evaluate and develop new strategies, specifically mutant selective EGFR specific degraders, determine whether such approaches, alone or in combination with existing ATP competitive EGFR inhibitors, overcome and/or more effectively limit the emergence of drug resistance than successive single agent treatments.
The goal of this project is to develop therapies to improve the outcome of patients with advanced EGFR mutant lung cancer. EGFR targeted therapies are the standard of care for patients with advanced EGFR mutant lung cancer. However, no patient is cured with existing EGFR targeted therapies. We will develop and test new strategies to target EGFR with the goal of prioritizing compounds that can both treat cancers that are currently resistant to all existing clinical EGFR inhibitors and those that can complement existing EGFR inhibitors by delaying or preventing the emergence of drug resistance.
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