Abstract B33: Tgif inactivation defines a synthetic lethal interaction among oncogenic Kras and Twist1 in pancreatic ductal adenocarcinoma

Abstract

Abstract The homeodomain protein TGIF function as a potent inhibitor of transforming growth factor beta (TGF-β) cytostatic signaling, whose inactivation is deemed instrumental to the pathogenesis and progression of pancreatic ductal adenocarcinoma (PDAC) driven by oncogenic Kras. Surprisingly, we found that deletion of Tgif in the context of mutant Kras (KrasG12D) expression culminated in the development of highly metastatic PDAC, despite leading to hyperactivation of TGF-(β/Smad) signaling. Mechanically, we found that TGIF associated with and antagonized Twist1 by a process involving Smad4, a tumor suppressor that is frequently inactivated in human PDAC. Along these lines, Twist1 overexpression synergized with KrasG12D to induce PDAC progression, whereas its ablation completely blocked the malignant phenotype driven by the combined KrasG12D expression and TGIF ablation. Thus, by demonstrating that TGIF functions as a tumor suppressor in PDAC owing to its ability to antagonize the pro-malignant transcription factor Twist1, our studies provide key insights into the role of Twist1 that could be exploited to design synthetic lethal therapeutics against oncogenic Kras, which has proven so far to be intractable. Citation Format: Parash Parajuli, Purba Singh, Zhe Wang, Santosh Kumar, Lena Li, Sailaja Eragamreddi, Thien Ly Nguyen, Subhi Talal Younes, Xu Zhang, Keli Xu, Mohammed Razzaque, Céline Prunier, Azeddine Atfi. Tgif inactivation defines a synthetic lethal interaction among oncogenic Kras and Twist1 in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B33.