Thursday, November 21, 2024
11/21/2024
Project Summary Pharmacological targeting of driver receptor tyrosine kinases (RTKs) can yield strong clinical responses, but lung cancer patients treated with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitors inevitably experience disease recurrence due to acquired resistance. More and better generations of RTK- targeting molecular therapies are developed, but still acquired resistance remains as a major and persistent clinical challenge. Checkpoint blockade immunotherapies are used to treat lung cancer, yet lung cancer patients with EGFR mutations and ALK rearrangements have low response rates. We have mapped the protein networks in EGFR- mutant and ALK-rearranged lung cancers, and shown growth factor bound protein 2 (GRB2) is a key oncogenic driver that causes acquired resistance to EGFR or ALK targeted therapies. The recent discovery of covalent targeted therapies for KRAS G12C offers an unprecedented opportunity to target KRAS directly. However, the resistance against KRAS G12C drugs is being observed in the treatment of KRAS-mutant lung cancer patients. A genome-wide analysis shows the activation of RTK signaling pathways and that GRB2 is a crucial gene for KRAS G12C drug resistance. To overcome this problem, we will develop the first drug that selectively degrades GRB2 and disrupts GRB2 interactions with driver RTKs. In preliminary studies, we have obtained a potent GRB2 binder TX-1-124 and solved the crystal structure of GRB2 bound with this compound. In this R21 application, we will design and synthesize the first-in-class cell-permeable proteolysis-targeting chimeras (PROTACs) to degrade intracellular GRB2, and evaluate potency of new GRB2-PROTACs against EGFR-mutant, ALK-rearranged, and KRAS G12C lung cancer cells including those cells resistant to first-line EGFR-, ALK- and KRAS G12C targeted therapies. The success of this project will offer the proof-of-concept that pharmacological downregulation of GRB2 using GRB2-PROTACs will block oncogenic RTK signaling and overcome acquired resistance mediated by RTK pathway activation or reactivation. The Specific Aim is the design, synthesis, and characterization of GRB2- PROTACs based on GRB2 binder TX-1-124.
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