Abstract LB-122: PIM1 kinase inhibition halts the growth of MYC-overexpressing triple-negative breast tumors
Authors: Horiuchi Dai , Zhou Alicia Y. , Corella Alexandra N. , Yau Christina , Lawson Devon A. , Bazarov Alexey V. , Yaswen Paul , McManus Michael T. , Werb Zena , Welm Alana L. , Goga Andrei 
Published: May 2015

Abstract
The proto-oncogene MYC affects diverse cellular processes ranging from cell proliferation, metabolism, to pluripotency of embryonic stem cells. While de-regulated MYC signaling has been commonly identified in a variety of human malignancies, no therapeutic strategies have been clinically established to specifically target tumors that present elevated MYC expression. We have previously reported that triple-negative (TN) breast cancers, which lack the expression of predictive biomarkers of response (i.e., estrogen/progesterone receptors, human epidermal growth factor receptor 2), exhibit significantly elevated MYC expression as well as MYC pathway activation (Horiuchi, D., et al. 2012 JEM). To understand the vulnerabilities of TN tumors, we performed a kinome synthetic-lethal shRNA screen in human mammary epithelial cells in which MYC activity can be controlled (i.e., HMEC-MycER cells). The screen yielded 10+ potential synthetic lethal partners of MYC, including recently described AMPK-related kinase 5 (Liu, L., et al. 2012. Nature). One of our top hits was the proto-oncogene PIM1, a non-essential serine/threonine kinase previously shown to be a genetic enhancer of MYC in transgenic mouse models of lymphomas and prostate cancer. Our bioinformatics studies performed on four independent clinical cohorts (n: 146 ∼ 683 patients each) showed that in all cohorts both MYC and PIM1 were significantly enriched in the TN populations. PIM1 expression was correlated with that of MYC in three out of the four cohorts. Furthermore, we found that PIM1 overexpression alone was a poor prognostic factor associated with diminished recurrence-free survival. Our in vivo efficacy studies using conventional as well as novel “human-in-mouse,” patient derived orthotopic xenograft (PDX) models demonstrated that PIM was essential for the growth of MYC-overexpressing human TN tumors. In the PDX tumors, PIM inhibition nearly completely arrested tumor growth, which was associated with significant up-regulation of an endogenous cell cycle inhibitor p27, a known PIM1 substrate, down-regulation of protein synthesis machinery, and inhibition of MYC activity itself. These observations held true in a panel of breast cancer cell lines, and elevating the p27 expression alone was sufficient to inhibit cancer cell proliferation. Thus, our findings warrant the use of PIM kinase inhibitors in treating TN tumors that exhibit the elevated expression of MYC and/or PIM.
Citation Format: Dai Horiuchi, Alicia Y. Zhou, Alexandra N. Corella, Christina Yau, Devon A. Lawson, Alexey V. Bazarov, Paul Yaswen, Michael T. McManus, Zena Werb, Alana L. Welm, Andrei Goga. PIM1 kinase inhibition halts the growth of MYC-overexpressing triple-negative breast tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-122. doi:10.1158/1538-7445.AM2014-LB-122