Abstract 3755: PDGF-induced tumor cell growth despite VEGF/EGF inhibition and absence of PDGF receptor expression in colon cancer

Abstract

Abstract Anti-Epithelial/Vascular Endothelial Growth Factor (EGF/VEGF)-targeted therapy plays important roles in advanced stage colorectal cancer (CRC) patients but fails to show clinical efficacy in specific subgroups which lack of clear underlying mechanisms. In vitro studies indicated that cross-talk or alternative receptor/ligand activities can bypass anti-growth factor signaling arrest and therefore may explain failure of monoclonal antibody (mAb) targeted therapy. In this study we analyzed effects of Platelet Derived Growth Factor (PDGF)-mediated bypassed signaling in CRC. We first investigated human UICC (Union for International Cancer Control ) stage I-IV tumors (n=46) from our Center and found increased PDGFRβ and VEGFR1/2 gene expression (p<0.01/p<0.001). Interestingly, further analysis on human HT29 colon cancer in vitro showed upregulated VEGFR1/2 expression upon VEGF stimulation. This was even more pronounced upon stimulation with PDGF. Inhibition of VEGFR2 and EGFR resulted in decreased HT29 cell proliferation, while additional treatment with VEGF and particularly PDGF attenuated the inhibiting effect and resulted in altered downstream signaling events. Treatment with the tyrosine kinase inhibitor Regorafenib alone, that blocks VEGFR/EGFR+PDGFR, prevented PDGF and VEGF-induced proliferation. This effect was not observed for either VEGFR2 mAb treatment with Ramucirumab or EGFR mAb therapy with Cetuximab. To conclude, PDGF-induced human colon cancer proliferation in the absence of PDGFR and simultaneously inhibited VEGFR2 and EGFR expression in HT29 colon cancer cells suggests bypassed alternative PDGF receptor partners for ligand binding on the tumor cell surface and subsequent intracellular signaling. This may explain failure of anti-VEGF/EGF-targeted monoclonal antibody therapies in CRC patient subgroups and underlines the necessity to effectively inhibit PDGF-mediated signaling events beside VEGF/EGF blockade in patients with increased PDGF expression within their tumors. Citation Format: Romana Moench, Martin Gasser, Karol Nawalaniec, Tanja Grimmig, Minghua Cao, Yueming Luo, Li-Li Hsiao, Ana Maria Waaga-Gasser. PDGF-induced tumor cell growth despite VEGF/EGF inhibition and absence of PDGF receptor expression in colon cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3755.