Abstract 1758: Resistance to cancer therapy via upregulation of the NRP2/VEGF-C axis can be neutralized by ATYR2810
Authors: Barber Alison , Xu Zhiwen , Eide Lisa , Polizzi Clara , Pastenes Max , Guy Lauren , Stamps Jasmine , Hamel Kristina , Fogassy Zachary , Klopp-Savino Sofia , Chong Esther , Qing Yang , Glendening Lara , Burkart Christoph , Nangle Leslie 
Published: April 2023

Abstract
Introduction: Intrinsic or acquired resistance to cancer therapy is a major problem in the treatment of many cancers. Therapy-resistant cancer cells are able to evade the effect of cancer drugs, resulting in highly aggressive clones that can cause poor long-term prognosis. Neuropilin-2 (NRP2) is a cell surface receptor that acts as a co-receptor for vascular endothelial growth factor (VEGF) and has been shown to be associated with therapy resistance. The VEGF-C signaling pathway has also been linked to chemoresistance in several cancer types including breast, bladder, and gastric cancer. Previously we have shown that ATYR2810—a highly specific humanized monoclonal antibody that blocks NRP2/VEGF-C signaling—sensitizes triple negative breast cancer (TNBC), a highly aggressive and chemoresistant subtype of breast cancer, to chemotherapy and targeted anti-VEGF therapy both in vitro and in vivo. In this study we examined the role of enhanced VEGF-C signaling in tumor growth and therapeutic resistance, and the ability of ATYR2810 to neutralize these effects using in vivo models for lung and kidney cancers.
Results: We generated a stable VEGF-C overexpressing non-small cell lung cancer (NSCLC) cell line and found that tumor growth was enhanced by increased VEGF-C signaling. Importantly, ATYR2810 monotherapy counteracted this VEGF-C-driven enhanced tumor growth as tumor growth inhibition was increased in the VEGF-C overexpressing tumors compared to control tumors. Further, VEGF-C overexpression was also found to enhance resistance to platinum-based chemotherapy in this model. However, sensitivity to chemotherapy was restored when ATYR2810 was used in combination with cisplatin. In clear cell renal cell carcinoma (ccRCC), the use of sunitinib—a small molecule inhibitor that inhibits the signaling of several receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptors (VEGFRs)—has reportedly been associated with the upregulation of VEGF-C and NRP2 expression as well as increased metastasis. In line with this, we found that the use of sunitinib leads to increased levels of circulating VEGF-C in the serum of ccRCC xenograft mice. The use of ATYR2810 in combination with sunitinib was found to act synergistically to inhibit tumor growth in ccRCC xenograft tumors leading to complete tumor regression in some animals.
Conclusions: Here we demonstrate that high levels of VEGF-C expression increase tumor dependency on the VEGF-C/NRP2 signaling axis thereby promoting tumor growth and chemoresistance. ATYR2810 counteracts the aggressive traits of tumors expressing high levels of VEGF-C resulting in enhanced tumor growth inhibition and sensitivity to both chemotherapy and targeted therapy.
Citation Format: Alison Barber, Zhiwen Xu, Lisa Eide, Clara Polizzi, Max Pastenes, Lauren Guy, Jasmine Stamps, Kristina Hamel, Zachary Fogassy, Sofia Klopp-Savino, Esther Chong, Yang Qing, Lara Glendening, Christoph Burkart, Leslie Nangle. Resistance to cancer therapy via upregulation of the NRP2/VEGF-C axis can be neutralized by ATYR2810 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1758.