Thursday, December 26, 2024
12/26/2024
PROJECT ABSTRACT Focal Adhesion Kinase (FAK) is a multifunctional non-receptor tyrosine kinase and scaffolding protein that is overexpressed in numerous solid tumors including melanoma, while minimally expressed in normal tissue. FAK has been widely investigated as a cancer drug target due its contribution in multiple aspects of tumor progression, including adhesion, invasion, proliferation, survival, metastasis, angiogenesis, and immune cell suppression. However, development of FAK inhibitors has largely focused on inhibition of the kinase enzyme of FAK opposed to inhibition of key scaffolding interactions. Particularly, limited efforts have been made at the discovery and biological evaluation of inhibitors of the focal adhesion targeting (FAT) scaffolding domain of FAK, the domain required for FAK localization to focal adhesions. During this period of support, we have identified the first discovered stapled peptide-based FAK inhibitor (UA-1907) that binds to and co-crystallizes with the FAT domain, and competitively inhibits FAK-paxillin binding. We have identified a myristoylated derivative (UA-2012) with improved cellular potency, favorable drug-like properties, and in vivo efficacy; and developed a bivalent peptide (UA-2023) with low nanomolar binding to FAT. However, the mechanistic differences between these novel FAT domain peptides and traditional FAK-kinase inhibitors on perturbation of focal adhesion complexes and the FAK interactome have yet to be elucidated. Furthermore, we have preliminary data showing that FAT inhibition provides selective anti-cancer effects in NRAS mutant melanoma cells. Melanoma is the deadliest form of skin cancer and there are no current effective targeted therapies against NRAS mutant melanoma, which represents ~30% of all patients. We hypothesize that FAK FAT domain inhibitors have distinct biological effects on the focal adhesion complex in cancer cells compared to FAK kinase inhibitors; and cancer cells with alterations in NRAS signaling pathways have a molecular dependence on FAK FAT scaffolding for survival, thus promoting selective anti-cancer efficacy. In specific aim 1, we will identify the unique differences between FAK FAT scaffold inhibitors and FAK kinase inhibitors on modulation of the focal adhesion complex and the FAK interactome. In specific aim 2, we will define the molecular mechanisms of sensitivity/resistance to FAK FAT inhibition in melanoma cells with activating mutations in NRAS and BRAF pathways. In specific aim 3, we will evaluate in vivo efficacy of novel FAK FAT domain inhibitors in mouse models of NRAS and BRAF driven cancer. Overall, in this project we will utilize FAT stapled peptides to validate that FAT domain targeting provides additional biological efficacy on the focal adhesion complex compared to FAK- kinase inhibitors and that NRAS mutant melanoma has a unique sensitivity to FAK FAT inhibition. .
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