Abstract B04: IKBKE integrates Gli and mTOR-AKT activation during Kras-induced pancreatic tumorigenesis

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest malignancies lacking effective therapeutic strategies. Here we show that the non-canonical IB-related kinase, IKBKE, acts downstream of the Gli transcription factors and engages in reciprocal regulation of Gli signaling in pancreatic cancer cells. We find that loss of IKBKE inhibits the initiation and progression of pancreatic tumors in mice carrying pancreatic specific KRAS activation. Mechanistically, IKBKE does not play a major role in NF-B activation in pancreatic cancer; but is critical for AKT activation in vivo. Moreover, we find that IKBKE promotes reactivation of AKT post-inhibition of mTOR in PDAC cells, and that combined inhibition of IKBKE and mTOR synergistically blocks pancreatic tumor growth. Together, our findings highlight the functional interaction of IKBKE with Hh/Gli and mTOR/AKT signaling in pancreatic cancer, and suggest IKBKE inhibition as a strategy to improve efficacy of mTOR inhibitors in the clinic.Citation Format: Mihir Rajurkar, Martin Fernandez-Zapico, Brian Lewis, Junhao Mao. IKBKE integrates Gli and mTOR-AKT activation during Kras-induced pancreatic tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B04.

Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Rajurkar, M., Fernandez-Zapico, M., Lewis, B., Mao, J. Tags: Signaling Pathways: Hedgehog: Poster Presentations - Proffered Abstracts Source Type: research