PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression

Dai Horiuchi*, Roman Camarda, Alicia Y. Zhou, Christina Yau, Olga Momcilovic, Sanjeev Balakrishnan, Alexandra N. Corella, Henok Eyob, Kai Kessenbrock, Devon A. Lawson, Lindsey A. Marsh, Brittany N. Anderton, Julia Rohrberg, Ratika Kunder, Alexey V. Bazarov, Paul Yaswen, Michael T. McManus, Hope S. Rugo, Zena Werb, Andrei Goga

*Corresponding author for this work

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Abstract

Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC-an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes-is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors. Direct inhibition of the oncogenic transcriptional activity of MYC has been challenging to achieve. Here, by conducting a shRNA screen targeting the kinome, we identified PIM1, a non-essential serine-threonine kinase, in a synthetic lethal interaction with MYC. PIM1 expression was higher in TN tumors than in RP tumors and was associated with poor prognosis in patients with hormone-and HER2-negative tumors. Small-molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic mouse models of breast cancer by inhibiting the oncogenic transcriptional activity of MYC and restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that have elevated MYC expression.

Original languageEnglish (US)
Pages (from-to)1321-1329
Number of pages9
JournalNature Medicine
Volume22
Issue number11
DOIs
StatePublished - Nov 1 2016

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Horiuchi, D., Camarda, R., Zhou, A. Y., Yau, C., Momcilovic, O., Balakrishnan, S., Corella, A. N., Eyob, H., Kessenbrock, K., Lawson, D. A., Marsh, L. A., Anderton, B. N., Rohrberg, J., Kunder, R., Bazarov, A. V., Yaswen, P., McManus, M. T., Rugo, H. S., Werb, Z., & Goga, A. (2016). PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression. Nature Medicine, 22(11), 1321-1329. https://doi.org/10.1038/nm.4213