TY - JOUR
T1 - Inhibition of a pancreatic cancer model by cooperative pairs of clinically approved and experimental antibodies
AU - Maron, Ruth
AU - Schechter, Bilha
AU - Nataraj, Nishanth Belugali
AU - Ghosh, Soma
AU - Romaniello, Donatella
AU - Marrocco, Ilaria
AU - Noronha, Ashish
AU - Yarden, Yosef
AU - Sela, Michael
N1 - We thank Dr. Rachel Heiblum for statistical analyses. This work was supported by grants from the European Research Council, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Moross Integrated Cancer Center and Estate of Flora Frank. D.R. and I.M. acknowledge the support of the Sergio Lombroso Foundation. M.S. is the incumbent of the W. Garfield Weston Chair. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair.
PY - 2019/5/21
Y1 - 2019/5/21
N2 - By year 2025 pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer related death. However, other than improved chemotherapy and a small molecule inhibitor of the epidermal growth factor receptor (EGFR), no targeted drugs are currently available. Repurposing of approved drugs might offer a rapid solution. We employed an animal PDAC model, expressing a mutant and a wild type form of p53 and KRAS, respectively. Cetuximab, a clinically approved anti-EGFR monoclonal antibody (mAb) weakly inhibited PDAC xenografts, similar to trastuzumab, a mAb against HER2, a co-receptor of EGFR. Because the combination of cetuximab and trastuzumab only moderately enhanced the anti-tumor effects, we combined each with a home-made mAb to the same receptor and identified two cooperative pairs. The pair of trastuzumab and a murine anti-HER2 mAb better than the anti-EGFR pair inhibited PDAC xenografts, although HER2's abundance in our model is 15-fold lower than the level of EGFR. In vitro studies attribute cooperation to forced receptor endocytosis/degradation and inhibition of both DNA synthesis and cell migration. Taken together, our results identify cooperative pairs of anti-PDAC antibodies and highlight potential mechanisms of anti-tumor effects. (C) 2019 Published by Elsevier Inc.
AB - By year 2025 pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer related death. However, other than improved chemotherapy and a small molecule inhibitor of the epidermal growth factor receptor (EGFR), no targeted drugs are currently available. Repurposing of approved drugs might offer a rapid solution. We employed an animal PDAC model, expressing a mutant and a wild type form of p53 and KRAS, respectively. Cetuximab, a clinically approved anti-EGFR monoclonal antibody (mAb) weakly inhibited PDAC xenografts, similar to trastuzumab, a mAb against HER2, a co-receptor of EGFR. Because the combination of cetuximab and trastuzumab only moderately enhanced the anti-tumor effects, we combined each with a home-made mAb to the same receptor and identified two cooperative pairs. The pair of trastuzumab and a murine anti-HER2 mAb better than the anti-EGFR pair inhibited PDAC xenografts, although HER2's abundance in our model is 15-fold lower than the level of EGFR. In vitro studies attribute cooperation to forced receptor endocytosis/degradation and inhibition of both DNA synthesis and cell migration. Taken together, our results identify cooperative pairs of anti-PDAC antibodies and highlight potential mechanisms of anti-tumor effects. (C) 2019 Published by Elsevier Inc.
UR - http://www.scopus.com/inward/record.url?scp=85063743820&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.bbrc.2019.03.204
DO - https://doi.org/10.1016/j.bbrc.2019.03.204
M3 - مقالة
SN - 0006-291X
VL - 513
SP - 219
EP - 225
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -