Abstract 3878: Musashi-2 (MSI2) regulation of ERBB family proteins in non-small cell lung cancer (NSCLC)

Abstract

Abstract The purpose of this study is to establish whether a new signaling axis we recently described can be targeted to improve patient survival in lung cancer, one of the leading causes of death worldwide, with over 1.6 million deaths annually. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. A small number of targeted therapies have been shown to be useful in lung cancer, including inhibitors of EGFR, but these are typically only active in a subset of tumors that maintain epithelial characteristics. Musashi-2 (MSI2), an RNA-binding protein that regulates mRNA translation, has been linked to maintenance of a stem cell state in multiple hematologic and solid tumor malignancies. We recently established (Kudinov et al, PNAS 2016, PMID:27274057) that MSI2 is elevated in a subset of NSCLC tumor upon progression and drives NSCLC metastasis, in part based on activity supporting a TGF-beta/SMAD3/claudin signaling cascade that enhances epithelial-mesenchymal transition (EMT). Using reverse phase protein array (RPPA) analysis of MSI2-depleted versus control KrasLA1/+;P53R172HΔG/+ murine NSCLC cell line models identified a significant 2.7-fold upregulation of HER3 upon MSI2 depletion. Negative MSI2-dependent regulation of ERBB3 protein expression was confirmed in multiple additional murine and human KRAS-dependent NSCLC models, based on analysis of MSI2 depletion or overexpression. In contrast, MSI2 positively regulated expression of the EGFR/ERBB1 protein in the same models. In detailed analysis, we have addressed the mechanism by which MSI2 regulates expression of the ERBB group of receptor tyrosine kinases. In addition, these data suggested the hypothesis that MSI2 expression might predict response to EGFR-targeted inhibitors, and that dual targeting of MSI2 and EGFR might be therapeutically valuable. We will present data on the activity of EGFR inhibitors in the context of depleted or elevated MSI2 expression, and the effect of combining inhibition of EGFR with recently developed MSI2 inhibitors. In summary, these results for the first time indicate a role of MSI2 in supporting EGFR expression in NSCLC and suggest that MSI2 may drive NSCLC development and progression in part via EGFR, and may modulate response to EGFR-targeted agents. Citation Format: Alexander Kudinov, Alexander Deneka, Anna N. Nikonova, Emmanuelle Nicolas, Vladislav A. Korobeynikov, Ilya G. Serebriiskii, John Karanicolas, Erica A. Golemis, Yanis Boumber. Musashi-2 (MSI2) regulation of ERBB family proteins in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3878. doi:10.1158/1538-7445.AM2017-3878