Abstract LB-310: PYK2 as a therapeutic target for pancreatic cancer
| Autor: | Guangming Chen, Jing Hu, Xuan Gao, Chenxi Gao, Dennis Han Zhang, Shih-Fan Kuan |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
YAP1
Oncology Cancer Research Hippo signaling pathway medicine.medical_specialty endocrine system diseases Effector Wnt signaling pathway Biology medicine.disease medicine.disease_cause digestive system diseases Tyrosine kinase 2 Pancreatic cancer Internal medicine medicine Cancer research Phosphorylation KRAS |
| Zdroj: | Cancer Research. 77:LB-310 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2017-lb-310 |
| Popis: | Since nearly 100% of pancreatic ductal adenocarcinoma (PDAC) carried mutational activation of KRAS, KRAS and its effectors are theoretically ideal candidates for PDAC therapeutic intervention. Unfortunately, attempts to directly inhibit oncogenic KRAS or known RAS effector pathways have been either unsuccessful or proven ineffective. As a result, there is significant interest in identifying novel downstream effectors of oncogenic KRAS signaling that could be amenable to pharmacologic intervention. Our results suggest that PYK2 (proline-rich tyrosine kinase 2, a non-receptor cytoplasmic tyrosine kinase) is a novel downstream mediator of mutant KRAS signaling and a new actionable therapeutic target for PDAC. Specifically, our studies revealed: (1) mutant KRAS activated PYK2 gene transcription in a YAP1 (Yes-associated protein 1)-dependent manner. Hippo pathway effector YAP1 is a transcription cofactor and a powerful downstream effector of mutant KRAS in PDAC. (2) PYK2 levels were drastically elevated in mouse PanINs (pancreatic intraepithelial neoplasia) and human PDAC tissues. (3) Functionally, Whole-body deletion of PYK2, even heterozygous deletion, remarkably suppressed PanIN formation and progression to PDAC in the Pdx1-Cre KRASG12D mice model. Further, knockdown of PYK2 abrogated tumor growth in a PDAC cell line xenograft model, indicating that PYK2 is required for PDAC maintenance. (4) Mechanistically, PYK2 directly phosphorylated β-catenin at tyrosine (Y) 654 to promote the Wnt/β-catenin pathway and increased RelA/p65 phosphorylation at serine (S) 536 to promote the NF-κB pathway in PDAC cells. Because both pathways are essential for PDAC development in mice, we propose that PYK2 contributes to PDAC through upregulating Wnt/β-catenin and NF-κB pathways. Overall, our study has revealed that PYK2 is a new actionable target for treating PDAC. Citation Format: Jing Hu, Chenxi Gao, Guangming Chen, Xuan Gao, Dennis H. Zhang, Shih-Fan Kuan. PYK2 as a therapeutic target for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-310. doi:10.1158/1538-7445.AM2017-LB-310 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|