TY - JOUR
T1 - Examination of HER3 targeting in cancer using monoclonal antibodies
AU - Gaborit, Nadege
AU - Abdul-Hai, Ali
AU - Mancini, Maicol
AU - Lindzen, Moshit
AU - Lavi, Sara
AU - Leitner, Orith
AU - Mounier, Lucile
AU - Chentouf, Myriam
AU - Dunoyer, Sai
AU - Ghosh, Manjusha
AU - Larbouret, Christel
AU - Chardes, Thierry
AU - Bazin, Herve
AU - Pelegrine, Andre
AU - Sela, Michael
AU - Yarden, Yosef
AU - Abdul-Haia, Ali
AU - Pèlegrin, André
N1 - Israel Cancer Research Fund; M. D. Moross Cancer Research Institute; Dr. Miriam and Sheldon G. Adelson Medical Research FoundationWe thank Bilha Schechter and Ruth Maron for their insightful advice regarding the in vivo experiments; Yaniv Levi for taking care of the animals; and both Hedva Hamawi and Ziv Landau for their assistance in the hybridoma generation process. Our laboratories are supported by the Israel Cancer Research Fund, the M. D. Moross Cancer Research Institute, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair. M.S. is the incumbent of the W. Garfield Weston Chair.
PY - 2015/1/20
Y1 - 2015/1/20
N2 - The human EGF receptor (HER/EGFR) family of receptor tyrosine kinases serves as a key target for cancer therapy. Specifically, EGFR and HER2 have been repeatedly targeted because of their genetic aberrations in tumors. The therapeutic potential of targeting HER3 has long been underestimated, due to relatively low expression in tumors and impaired kinase activity. Nevertheless, in addition to serving as a dimerization partner of EGFR and HER2, HER3 acts as a key player in tumor cells' ability to acquire resistance to cancer drugs. In this study, we generated several monoclonal antibodies to HER3. Comparisons of their ability to degrade HER3, decrease downstream signaling, and inhibit growth of cultured cells, as well as recruit immune effector cells, selected an antibody that later emerged as the most potent inhibitor of pancreatic cancer cells grown as tumors in animals. Our data predict that anti-HER3 antibodies able to intercept autocrine and stroma-tumor interactions might strongly inhibit tumor growth, in analogy to the mechanism of action of anti-EGFR antibodies routinely used now to treat colorectal cancer patients.
AB - The human EGF receptor (HER/EGFR) family of receptor tyrosine kinases serves as a key target for cancer therapy. Specifically, EGFR and HER2 have been repeatedly targeted because of their genetic aberrations in tumors. The therapeutic potential of targeting HER3 has long been underestimated, due to relatively low expression in tumors and impaired kinase activity. Nevertheless, in addition to serving as a dimerization partner of EGFR and HER2, HER3 acts as a key player in tumor cells' ability to acquire resistance to cancer drugs. In this study, we generated several monoclonal antibodies to HER3. Comparisons of their ability to degrade HER3, decrease downstream signaling, and inhibit growth of cultured cells, as well as recruit immune effector cells, selected an antibody that later emerged as the most potent inhibitor of pancreatic cancer cells grown as tumors in animals. Our data predict that anti-HER3 antibodies able to intercept autocrine and stroma-tumor interactions might strongly inhibit tumor growth, in analogy to the mechanism of action of anti-EGFR antibodies routinely used now to treat colorectal cancer patients.
KW - Antibody combination
KW - Cancer therapy
KW - HER3
KW - Signal transduction
KW - Tyrosine kinase
UR - https://www.scopus.com/pages/publications/84921417367
U2 - 10.1073/pnas.1423645112
DO - 10.1073/pnas.1423645112
M3 - مقالة
C2 - 25564668
SN - 0027-8424
VL - 112
SP - 839
EP - 844
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 3
ER -
SDG 3 Good Health and Well-being