IQGAP1 Maintains Pancreatic Ductal Adenocarcinoma Clonogenic Growth and Metastasis.

Abstract

IQ motif containing GTPase-activating protein 1 (IQGAP1) acts as a scaffold for aberrant mitogen-activated protein kinase (MAPK) signaling driven by KRAS mutations in pancreatic ductal adenocarcinoma (PDAC). We determined the role of IQGAP1 in clonogenic growth and metastasis in PDAC. We inhibited IQGAP1 expression using shRNA and assessed clonogenic growth, cell migration, and MAPK signaling in vitro and tumor initiation and metastasis in vivo. The efficacy of a peptide mimicking the IQGAP1 WW domain that binds and inhibits ERK1/2 was determined in vitro and in vivo. IQGAP1 loss inhibited clonogenic growth and migration of KRAS-dependent PDAC cells by disrupting MAPK signaling. In mice, IQGAP1 knockdown decreased tumor-initiating cell frequency and metastasis. WW peptide treatment inhibited clonogenic growth and in vivo tumor growth. Pancreatic ductal adenocarcinoma clonogenic growth, metastasis, and tumor initiation are dependent on MAPK signaling via IQGAP1. Treatment with a WW peptide disrupts IQGAP1 function and represents a novel targeting strategy for PDAC.