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Characterization of activating mutations of NOTCH3 in T cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies

Bernasconi-Elias, Paula and Hu, Tiancen and Jenkins, David and Firestone, Brant and Gans, Sara and Kurth, Esther and Capodieci, Paola and Deplazes-Lauber, Joelle and Petropoulos, Konstantin and Thiel, Phillip and Ponsel, Dirk and Choi, Sung Hee and Lemotte, Peter and London, Anne and Goetcshkes, Margaret and Nolin, Erin and Jones, Michael and Slocum, Kelly and Kluk, Michael and Weinstock, David and Christodoulou, Alexandra and Weinberg, Olga and Jaehrling, Jan and Ettenberg, Seth and Buckler, Alan and Blacklow, Stephen and Aster, Jon and Fryer, Christy (2016) Characterization of activating mutations of NOTCH3 in T cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene. ISSN 0950-92321476-5594

Abstract

Notch signaling is an evolutionarily conserved pathway that regulates a diverse set of biological functions. Notch receptors have been implicated as oncogenic drivers in a number of different cancers, most notably NOTCH1 in T-cell acute lymphoblastic leukemia. In solid tumors the roles of various receptors in tumor initiation and progression are more complex. To characterize the role of NOTCH3 in human cancers we generated an antibody that detects the neo-epitope at the N-terminus of the gamma-secretase activated NOTCH3 intracellular domain (ICD3) and sequenced the negative regulatory region (NRR) and PEST (proline, glutamate, serine, threonine) domain coding regions of NOTCH3 in a large panel of cell lines. We characterize here several NOTCH3 tumor-associated mutations that result in activation of signaling. We also describe two new inhibitory antibodies that bind to the NOTCH3 NRR, and elucidate the structural basis for receptor inhibition by solving co-crystal structures of the antibodies in complex with the NRR. The antibodies exhibit potent anti-leukemic activity in cell lines and tumor xenografts harboring NOTCH3 activating mutations. Screening of primary T-cell acute lymphoblastic leukemia samples revealed that 2 of 40 tumors examined had evidence of active NOTCH3 signaling. Our studies provide additional insights into NOTCH3 activation and offer a path forward for identification of cancers that are likely to respond to therapy with NOTCH3 selective inhibitory antibodies.

Item Type: Article
Date Deposited: 17 Dec 2015 00:45
Last Modified: 04 Jul 2016 23:45
URI: https://oak.novartis.com/id/eprint/26589

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