Abstract 555: Loss of function Cbl-c mutations in solid tumors

Abstract

Abstract Receptor Tyrosine Kinase (RTK) signaling, which is essential for cellular growth and proliferation, can lead to malignant transformation and tumorigenesis when aberrantly activated. Cbl proteins (Cbl, Cbl-b, and Cbl-c) are a conserved family of RING finger (RF) ubiquitin ligases (E3) that negatively regulate the activity of several tyrosine kinases such as the EGFR. Cbl mutations have recently been identified in 5% of human myeloid neoplasms, with a majority of mutations clustered within the RF and linker domains. Cbl-c is the most recently identified Cbl protein and is exclusively expressed in epithelial cells. We recently identified a novel cDNA isolated from a mouse mammary tumor in the C3(1) Large T Antigen transgenic mouse model. This mutant cDNA encodes a protein that has a deletion in the RF domain of Cbl-c, thereby resembling known Cbl family mutations associated with myeloid neoplasias. Genomic analyses of both parental and transgenic lines show no evidence of germline mutation, suggesting that this mutation is most likely somatic. The mutant Cbl-c protein enhances transformation of NIH 3T3 cells when co-transfected with SV40 Large T Antigen. In overexpression studies, this mutant Cbl-c fails to mediate ubiquitination of activated EGFR and acts in a dominant negative manner to prevent ubiquitination of activated EGFR by wildtype Cbl proteins. Datamining also reveals Cbl-c mutations associated with human solid tumors. Cell-based analyses demonstrate a similar loss of E3 function in some of these human mutations. These data collectively suggest that, like Cbl mutations in myeloid neoplasms, loss of function Cbl-c mutants may also contribute to the pathogenesis of solid tumors in murine models and in humans. Citation Format: Silvano R. Daniels, Stephen C. Kales, Mariya Liyasova, Marion M. Nau, Phil E. Ryan, Jeffrey E. Green, Stanley Lipkowitz. Loss of function Cbl-c mutations in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 555.