title: PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression.
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.
authors: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.|Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.|Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.
authors: Dai
authors: D
authors: Horiuchi
authors: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.
authors: Roman
authors: R
authors: Camarda
authors: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.
authors: Alicia Y
authors: AY
authors: Zhou
authors: Department of Surgery, University of California, San Francisco, San Francisco, California, USA.|Cancer and Developmental Therapeutics Program, Buck Institute for Research on Aging, Novato, California, USA.
authors: Christina
authors: C
authors: Yau
authors: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.
authors: Olga
authors: O
authors: Momcilovic
authors: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.
authors: Sanjeev
authors: S
authors: Balakrishnan
authors: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.
authors: Alexandra N
authors: AN
authors: Corella
authors: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.
authors: Henok
authors: H
authors: Eyob
authors: Department of Anatomy, University of California, San Francisco, San Francisco, California, USA.
authors: Kai
authors: K
authors: Kessenbrock
authors: Department of Anatomy, University of California, San Francisco, San Francisco, California, USA.
authors: Devon A
authors: DA
authors: Lawson
authors: Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.|Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.
authors: Lindsey A
authors: LA
authors: Marsh
authors: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.
authors: Brittany N
authors: BN
authors: Anderton
authors: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.
authors: Julia
authors: J
authors: Rohrberg
authors: Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.|Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.
authors: Ratika
authors: R
authors: Kunder
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
authors: Alexey V
authors: AV
authors: Bazarov
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
authors: Paul
authors: P
authors: Yaswen
authors: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA.
authors: Michael T
authors: MT
authors: McManus
authors: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Hope S
authors: HS
authors: Rugo
authors: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.|Department of Anatomy, University of California, San Francisco, San Francisco, California, USA.
authors: Zena
authors: Z
authors: Werb
authors: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.|Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors: Andrei
authors: A
authors: Goga
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C493961:Cdkn1b protein, mouse; C489427:MYC protein, human; C489428:Myc protein, mouse; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D050760:Cyclin-Dependent Kinase Inhibitor p27; C496634:PIM1 protein, human; C496636:Pim1 protein, mouse; D051573:Proto-Oncogene Proteins c-pim-1