Abstract 213: Novel NOTCH3 activating mutations identified in tumors sensitive to OMP-59R5, a monoclonal antibody targeting the Notch2 and Notch3 receptors
| Autor: | Tracy Tang, Jalpa Shah, Jennifer Cain, Aaron K. Sato, Ann M. Kapoun, Belinda Cancilla, Breanna Wallace, Min Wang, Tim Hoey, Jie Wei, Austin L. Gurney, John Lewicki, Chris Muriel |
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| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | Cancer Research. 73:213-213 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2013-213 |
| Popis: | The Notch signaling pathway, driven by four Notch family receptors (NOTCH1-4) and five canonical Notch ligands (DLL1, DLL3, DLL4, JAG1, and JAG2) in humans, critically regulates key functions during embryonic development as well as stem cell maintenance and differentiation in adult tissues. Altered Notch signaling activity has been documented in many types of cancers; depending on the tumor type, Notch signaling can be oncogenic or tumor suppressing. Activating mutations in NOTCH1 have been identified in hematopoietic cancers including T-cell acute lymphoblastic leukemia and chronic lymphoblastic leukemia. With the advance in high-throughput genomic sequencing platforms, mutations in the NOTCH genes have also been identified in solid tumors, albeit at much lower frequencies. Here we report for the first time the identification of two activating mutations in NOTCH3. One is a frameshift mutation in the PEST domain, and the other a frameshift mutation in the ankyrin (ANK) domain. The PEST frameshift mutation leads to the production of C-terminally truncated NOTCH3 protein, and by Western Blotting of nuclear fractions of tumor tissues and Immunohistochemistry (IHC) we show that this mutant NOTCH3 accumulates stably in the nuclei of the breast tumor in which it was identified. Breast xenograft tumors carrying this mutation are highly sensitive to OMP-59R5, a ligand-blocking antibody targeting the Notch2 and Notch3 receptors, suggesting that the mutation, although activating, is still ligand dependent. Consistent with this finding, expression of this mutant NOTCH3 constructed by site-directed mutagenesis exhibits higher baseline activity compared to wild type NOTCH3 and is equally responsive to ligands in in vitro NOTCH reporter assays. We are not able to observe increased nuclear accumulation of the ANK frameshift mutant NOTCH3 in the colon tumor in which it was identified. However, in vitro the ANK mutant NOTCH3 has higher baseline activity than wild-type NOTCH3 in the absence of ligands and remains highly responsive to ligands. The colon xenograft tumors carrying this NOTCH3 ANK mutation are also sensitive to OMP-59R5 in in vivo efficacy studies. Taken together our data suggest that NOTCH3 is oncogenic in certain subtypes of tumors, and tumors with these activating mutations may predictive sensitivity to therapeutic antibodies targeting the receptor. Citation Format: Breanna Wallace, Min Wang, Chris Muriel, Jennifer Cain, Belinda Cancilla, Jalpa Shah, Jie Wei, Austin Gurney, John Lewicki, Aaron Sato, Tim Hoey, Tracy Tang, Ann M. Kapoun. Novel NOTCH3 activating mutations identified in tumors sensitive to OMP-59R5, a monoclonal antibody targeting the Notch2 and Notch3 receptors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 213. doi:10.1158/1538-7445.AM2013-213 |
| Databáze: | OpenAIRE |
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