An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development
Sunita Shankar, Jean C. Tien, Ronald F. Siebenaler, Seema Chugh, Vijaya L. Dommeti, Sylvia Zelenka-Wang, Xiaoming Wang, Ingrid J. Apel, Jessica Waninger, Sanjana Eyunni, Alice Xu, Malay Mody, Andrew Goodrum, Yuping Zhang, J.J.G. Tesmer, Rahul Mannan, Xuhong Cao, Pankaj Vats, Sethuramasundaram Pitchiaya, Stephanie J. Ellison, Jiaqi Shi, Chandan Kumar‐Sinha, Howard C. Crawford, Arul M. Chinnaiyan
Abstract
Abstract Both KRAS and EGFR are essential mediators of pancreatic cancer development and interact with Argonaute 2 (AGO2) to perturb its function. Here, in a mouse model of mutant KRAS-driven pancreatic cancer, loss of AGO2 allows precursor lesion (PanIN) formation yet prevents progression to pancreatic ductal adenocarcinoma (PDAC). Precursor lesions with AGO2 ablation undergo oncogene-induced senescence with altered microRNA expression and EGFR/RAS signaling, bypassed by loss of p53 . In mouse and human pancreatic tissues, PDAC progression is associated with increased plasma membrane localization of RAS/AGO2. Furthermore, phosphorylation of AGO2 Y393 disrupts both the wild-type and oncogenic KRAS-AGO2 interaction, albeit under different conditions. ARS-1620 (G12C-specific inhibitor) disrupts the KRAS G12C -AGO2 interaction, suggesting that the interaction is targetable. Altogether, our study supports a biphasic model of pancreatic cancer development: an AGO2 -independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an AGO2 -dependent phase wherein the mutant KRAS-AGO2 interaction is critical for PDAC progression.