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 outcome1. 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) tumors2. Direct inhibition of the oncogenic transcriptional activity of MYC has been challenging to achieve3. 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.
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This work was supported in part by grants from the US National Institutes of Health (K99CA175700 (D.H.), R00CA175700 (D.H.), 5T32DK007418 (R.C.), K99CA181490 (K.K.), ES019458 (P.Y. and Z.W.), U01CA168370 (M.T.M.), P30DK63720 (M.T.M.), R01CA180039 (Z.W.) and R01CA170447 (A.G.)), the Susan G. Komen Foundation (PDF15331114; J.R.), the UCSF Program for Breakthrough Biomedical Research (M.T.M.), an Innovative, Developmental, and Exploratory Award from the California Breast Cancer Research Program (17lB-0024; A.G.), an Era of Hope Scholar Award from the CDMRP Breast Cancer Research Program (W81XWH-12-1-0272 and W81XWH-16-1-0603; both to A.G.), an LLS Scholar Award (A.G.), a V-Foundation Award (A.G.), the Breast Cancer Research Foundation (H.S.R. and A.G.) and the Northwestern Medicine Catalyst Funds (D.H.). The authors thank A. Welm for her guidance with the use of the patient-derived orthotopic tumor xenograft models, J.W. Smyth for his assistance with the generation of the transgenic breast cancer cell lines, and D.B. Udy, C.L. Hueschen and A. Vasilopoulos for their assistance with microscopy. We thank S. Samson, C. Baas, H. Klein-Connolly and D. Roth for consumer advocacy support and feedback related to this project, and J.M. Bishop for his insights into the project and his mentorship to D.H.
The authors declare no competing financial interests.
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Horiuchi, D., Camarda, R., Zhou, A. et al. PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression. Nat Med 22, 1321–1329 (2016). https://doi.org/10.1038/nm.4213
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