CXCR2 signaling regulates KRAS(G12D)-induced autocrine growth of pancreatic cancer

// Abhilasha Purohit 1 , Michelle Varney 1 , Satyanarayana Rachagani 2 , Michel M. Ouellette 3 , Surinder K. Batra 1, 2, 3 , Rakesh K. Singh 1 1 Department of Pathology and Microbiology, 985900 Nebraska Medical Center, Omaha, NE, USA 2 Department of Biochemistry and Molecular Biology, 985870 Nebraska Medical Center, Omaha, NE, USA 3 Eppley Institute, 985950 Nebraska Medical Center, Omaha, NE, USA Correspondence to: Rakesh K. Singh, e-mail: rsingh@unmc.edu Keywords: KRAS (G12D) , PDAC, CXCR2, autocrine growth, ERK Received: August 05, 2015      Accepted: November 25, 2015      Published: January 13, 2016 ABSTRACT Pharmacological inhibition of RAS , the master regulator of pancreatic ductal adenocarcinoma (PDAC), continues to be a challenge. Mutations in various isoforms of RAS gene, including KRAS are known to upregulate CXC chemokines; however, their precise role in KRAS-driven pancreatic cancer remains unclear. In this report, we reveal a previously unidentified tumor cell-autonomous role of KRAS (G12D) -induced CXCR2 signaling in mediating growth of neoplastic PDAC cells. Progressively increasing expression of mCXCR2 and its ligands was detected in the malignant ductal cells of Pdx1-cre;LSL- Kras (G12D) mice. Knocking-down CXCR2 in KRAS (G12D) -bearing human pancreatic duct-derived cells demonstrated a significant decrease in the in vitro and in vivo tumor cell proliferation. Furthermore, CXCR2 antagonists showed selective growth inhibition of KRAS (G12D) -bearing cells in vitro. Intriguingly, both genetic and pharmacological inhibition of CXCR2 signaling in KRAS (G12D) -bearing pancreatic ductal cells reduced the levels of KRAS protein, strongly implying the presence of a KRAS-CXCR2 feed-forward loop. Together, these data demonstrate the role of CXCR2 signaling in KRAS (G12D) -induced growth transformation and progression in PDAC.