Investigation of a Novel Non-PROTAC Small-Molecule Degrader of Activated-EGFR Against Osimertinib-Resistant Non-Small Cell Lung Cancers
Abstract
Lung cancer is the most common cancer worldwide, accounting for 2.2 million new cases and 1.8 million deaths in 2020 (Globocan 2020). Lung cancer is also the leading cause of cancer related mortality amongst American military Veterans, and the 5-year survival rate is only about 15 percent. About one in four patients with lung cancer harbors mutations in the gene for the cancer-promoting protein EGFR (epidermal growth factor receptor). While these patients may initially respond to therapy with tyrosine kinase inhibitor (TKI) drugs such as erlotinib/afatinib/osimertinib that inhibit the catalytic activity of EGFR, at least 50% of the patients develop drug resistance, and their cancer recurs within a year. This resistance is often a result of additional mutations in the catalytic or kinase domain of EGFR that prevent drugs such as erlotinib from inhibiting the activity of the receptor thus allowing tumor cells to grow. In order for EGFR to promote tumor growth, it must interact with the ligand epidermal growth factor (EGF), levels of which can be very high around tumor cells. Upon binding with EGF, EGFR dimerizes and starts a cascade of signals that tell the tumor cells to grow and multiply. This dimerization process is different in tumor and normal cells. We have found that, if we mutate EGFR dimerization sites, the EGFR protein becomes unstable and disappears from cells, and the tumor cells die. We hypothesized that a small molecule capable of specifically binding at the dimer interface of ligand- bound EGFR and preventing dimerization in tumor cells will induce EGFR degradation and subsequent cell death. To test the hypothesis that EGFR degradation kills tumor cells more effectively than EGFR inhibition, we used the structure of the EGFR dimerization interface to develop a novel small molecule, DPI-503, which blocks EGF-induced EGFR dimerization and kills EGFR-driven cells in vitro. DPI-503 is orally bioavailable, has a good in vivo safety profile in mouse models, and shows single-agent activity in osimertinib-resistant mutant EGFR containing xenograft models. We now seek to assess the ability of DPI-503 to inhibit the growth of drug-resistant lung cancer in vivo, both as a single agent and in combination with chemo-radiotherapy. Our objective is to fully evaluate DPI-503 activity against cell lines engineered to express TKI-resistant EGFR mutants, delineate the difference between EGFR inhibition vs EGFR degradation, and evaluate the therapeutic potential of DPI-503 as a single agent as well as in combination with chemo/radiotherapy. Our long-term goal is to advance DPI-503 into the clinic to treat EGFR mutant TKI naïve and resistant lung cancers, while also defining future patient selection strategies for this genomic subpopulation. We strongly believe there is a significant new commercial opportunity with our approach to degrade EGFR protein itself rather than simply inhibit its signaling activity. Initially, we are focusing on osimertinib-refractory lung cancer patients. However, once DPI-503 is approved in this refractory setting, we expect to conduct head-to-head clinical trials in treatment naïve patients against the standard-of-care agents, since we believe the activity will be greater and the toxicity will be minimal compared to existing drugs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210552
Entities
People
- Mukesh K Nyati
Organizations
- United States Army
- University of Michigan