Wednesday, January 15, 2025
1/15/2025
Abstract: Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are a common cause of lung adenocarcinoma. Despite marked advances in targeted therapies for EGFR-mutant lung cancer, treatment-acquired resistance remains a major problem. Understanding and overcoming acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) and to other targeted therapies is a central problem in cancer medicine. Our long term goal is to develop more effective and better tolerated therapies for EGFR mutant lung cancer that yield durable responses. We reason that simultaneous treatment with multiple agents targeting mutant EGFR may prevent emergence of resistance mutations, leading to more durable responses. However, suitable compounds with alternative mechanisms of action have not previously been available. Like the vast majority of TKIs, all current EGFR TKIs target the ATP- site of the kinase. Our multidisciplinary research team has deep expertise in EGFR-mutant lung cancer and a record of successful inhibitor discovery. In the initial grant period, we developed highly potent allosteric inhibitors based on a phenylglycine scaffold that are effective as single agents against L858R/T790M and L858R/T790M/C797S EGFR variants in vitro and in mouse models of human non-small cell lung cancer. The distinct mechanism of action and binding site of these allosteric inhibitors, together with their lack of potency on WT EGFR and other protein kinases, makes them especially attractive as candidates for combination therapy. In this renewal, we will discover whether compounds that target the ATP and allosteric sites can indeed synergize to deliver unprecedented efficacy, tolerability and durability of responses. We pursue this goal through the following specific aims: Aim 1, We will develop a second chemical series of highly potent, mutant-selective allosteric EGFR inhibitors based on a benzodiazepinone scaffold. Aim 2, We will design and optimize complementary pairs of inhibitors that simultaneously bind the adjacent ATP and allosteric sites of mutant EGFR with a high degree of positive cooperativity. To our knowledge, highly cooperative, multi-site inhibition has not been previously explored in the context of therapeutic development. Aim 3, We will perform pre-clinical validation of allosteric EGFR inhibitors and complementary ATP-site/allosteric pairs, including testing their in vivo efficacy in xenograft models of EGFR mutant lung cancer and assessing the potential for resistance to arise in the context of dual targeting. Successful execution of these aims will provide proof of concept for a new therapeutic approach in EGFR mutant lung cancer.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).