Abstract 2162: Inhibition of pancreatic cancer cell and tumor growth using MET inhibitors in combination with inhibitors of downstream signaling mediators, MEK and PI3K.

Abstract

Abstract Oncogenic signaling through the receptor tyrosine kinase (RTK) MET has been implicated in driving tumor cell invasive growth. High expression of MET or its cognate ligand, the hepatocyte growth factor (HGF) have been associated with poor prognosis in multiple cancer types, including pancreatic cancer. MET has also been implicated in co-operative signaling with other RTKs, including those in the HER family. We examined the expression of MET and HGF in a panel of pancreatic cancer cell lines and examined the impact of MET activation on cell signaling. While most lines were uniformly positive for MET protein, 6/12 lines not co-expressing HGF and MET, and all sub-lines of the autocrine KP4 line, demonstrated constitutive phosphorylation of MET (p-MET) in normal growth conditions. All lines were positive for epidermal growth factor receptor (EGFR) protein and had basal levels of phosphorylated-EGFR (p-EGFR) with evidence of downstream activity in the MAPK and PI3K signaling pathways. Treatment of some lines expressing constitutive p-MET with the small molecule MET inhibitor GDC-0712 resulted in suppression of both p-MET and p-EGFR. However, treatment of these same lines with erlotinib resulted in no inhibition of p-EGFR or p-MET, strongly suggesting that MET activates EGFR phosphorylation. Co-suppression of MET with GDC-0712 or onartuzumab (MetMAb) and erlotinib resulted in greater inhibition than either agent alone. We assessed whether anti-tumor activity could be further improved by targeting downstream molecules of MET or EGFR signaling, including modulators of the Ras or PI3K pathways, in combination with MET inhibitors. Improved cell inhibition was seen with combinations of MET inhibitors and the MEK inhibitor GDC-0973 compared with either agent alone, with greater activity than combinations of MET and EGFR inhibitors. Analysis of the combination of MET inhibitors with GDC-0973 revealed that Ras signaling contributed to the stability of total MET levels, resulting in lower total p-MET burden when MEK was inhibited. The combination of MET and MEK inhibitors produced greater suppression of downstream signaling through ERK and the ribosomal S6 kinase, which resulted in better induction of the pro-apoptotic mediator Bim and induction of cleaved caspase 3. These effects were not seen with combinations of MET and PI3K inhibitors in vitro. Lastly, MET inhibitors were evaluated in combination with MEK, PI3K or EGFR inhibitors in pancreatic xenograft tumor models. The combination of MET and MEK inhibitors resulted in additive anti-tumor activity whereas there was little to no apparent increase in activity with combinations of MET and PI3K or EGFR inhibitors. These data provide evidence for an interplay between MET and mutant Ras signal transduction and provide a rationale for combination of MET and MEK inhibitors in the treatment of pancreatic cancer. Citation Format: Nai-Ying Yang, Jing Peng, Janet Tien, Mark Merchant. Inhibition of pancreatic cancer cell and tumor growth using MET inhibitors in combination with inhibitors of downstream signaling mediators, MEK and PI3K. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2162. doi:10.1158/1538-7445.AM2013-2162