Thursday, April 25, 2024
4/25/2024
Project Summary (as stated in parent grant) Pancreatic ductal adenocarcinoma (PDAC) is a devastating form of pancreatic cancer with dismal patient outcome. KRAS, which is commonly mutated in PDAC, is a driving oncogene in this disease. However, development of approaches to target KRAS has proven challenging and inhibitors targeting signaling networks downstream of KRAS such as the MAPK pathway have largely failed as single agents. The overall goal of this proposal is to use innovative chemical strategies to identify combination regimens in PDAC, which are urgently needed to improve patient survival. Combining CRISPR screens and epigenomic profiling, I identified that the YAP/TAZ/TEAD axis is a critical transcriptional node required for the bypass survival program upon KRAS loss or MEK inhibition. This data and published literature support the importance of directly targeting the YAP/TAZ/TEAD axis in PDAC. However, current YAP/TAZ/TEAD inhibitors have poor potency and off-target effects and genetic strategies to study critical transcription regulators have limited utility due to delays between protein loss and experimental measurement. To overcome these limitations, I developed a versatile tag-based technology platform known as the degradation tag (dTAG) system to induce rapid degradation of any target protein in cell lines and mouse models. The dTAG system enables evaluation of target protein loss with a small molecule degrader in a time-scale that is not possible with genetic approaches, facilitating evaluations of mutant KRAS, YAP and TAZ. In addition, the Gray laboratory developed a selective small molecule covalent TEAD inhibitor to irreversibly inactivate aberrant YAP/TAZ/TEAD signaling. The work proposed in this application will leverage the dTAG technology platform and a covalent TEAD inhibitor to establish the role of YAP/TAZ/TEAD in coordinating bypass survival in PDAC. In Aim 1, in the absence of direct YAP or TAZ inhibitors, I will use the dTAG system to define the direct YAP and TAZ transcriptional signaling program that promotes survival upon modulation of KRAS signaling. These experiments will demonstrate the potential of chemical degradation of YAP and TAZ and identify novel targetable vulnerabilities. In Aim 2, I will use PDAC cell lines and patient-derived organoid models to evaluate the translational potential of covalent TEAD inhibition as a combination regimen with KRAS signaling disruption. Integrating chemical biology, genome- scale analyses, and translational models of PDAC, I expect that PDAC-specific therapeutic insights will emanate from this work. To achieve these aims, I designed a 3-year plan that includes participation in scientific and career development meetings, workshops and coursework to further develop my cancer chemical biology and computational biology expertise. This career transition award will greatly facilitate my goal of leading a multidisciplinary research laboratory focused on addressing challenges in the treatment of pancreatic cancer.
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