TY - JOUR
T1 - PIM kinase inhibitor AZD1208 for treatment of MYC-driven prostate cancer
AU - N. Kirschner, Austin
AU - Wang, Jie
AU - Van Der Meer, Riet
AU - Anderson, Philip D.
AU - Franco-Coronel, Omar E.
AU - Kushner, Max H.
AU - Everett, Joel H.
AU - Hameed, Omar
AU - Keeton, Erika K.
AU - Ahdesmaki, Miika
AU - Grosskurth, Shaun E.
AU - Huszar, Dennis
AU - Abdulkadir, Sarki A.
N1 - Funding Information:
Part of this work was supported by an internal grant from the Department of Radiation Oncology at Vanderbilt University Medical Center to ANK. This work was supported by grants R01CA123484 and R01CA167966 from the National Cancer Institute (NCI) to SAA and by AstraZeneca.
PY - 2015/2/1
Y1 - 2015/2/1
N2 - Background: PIM1 kinase is coexpressed with c-MYC in human prostate cancers (PCs) and dramatically enhances c-MYC-induced tumorigenicity. Here we examine the effects of a novel oral PIM inhibitor, AZD1208, on prostate tumorigenesis and recurrence. Methods: A mouse c-MYC/Pim1-transduced tissue recombination PC model, Myc-CaP allografts, and human PC xenografts were treated with AZD1208 (n = 5-11 per group). Androgen-sensitive and castrate-resistant prostate cancer (CRPC) models were studied as well as the effects of hypoxia and radiation. RNA sequencing was used to analyze drug-induced gene expression changes. Results were analyzed with χ2 test. Student's t test and nonparametric Mann-Whitney rank sum U Test. All statistical tests were two-sided. Results: AZD1208 inhibited tumorigenesis in tissue recombinants, Myc-CaP, and human PC xenograft models. PIM inhibition decreased c-MYC/Pim1 graft growth by 54.3±39% (P <. 001), decreased cellular proliferation by 46±14% (P =. 016), and increased apoptosis by 326±170% (P =. 039). AZD1208 suppressed multiple protumorigenic pathways, including the MYC gene program. However, it also downregulated the p53 pathway. Hypoxia and radiation induced PIM1 in prostate cancer cells, and AZD1208 functioned as a radiation sensitizer. Recurrent tumors postcastration responded transiently to either AZD1208 or radiation treatment, and combination treatment resulted in more sustained inhibition of tumor growth. Cell lines established from recurrent, AZD1208-resistant tumors again revealed downregulation of the p53 pathway. Irradiated AZD1208-treated tumors robustly upregulated p53, providing a possible mechanistic explanation for the effectiveness of combination therapy. Finally, an AZD1208-resistant gene signature was found to be associated with biochemical recurrence in PC patients. Conclusions: PIM inhibition is a potential treatment for MYC-driven prostate cancers including CRPC, and its effectiveness may be enhanced by activators of the p53 pathway, such as radiation.
AB - Background: PIM1 kinase is coexpressed with c-MYC in human prostate cancers (PCs) and dramatically enhances c-MYC-induced tumorigenicity. Here we examine the effects of a novel oral PIM inhibitor, AZD1208, on prostate tumorigenesis and recurrence. Methods: A mouse c-MYC/Pim1-transduced tissue recombination PC model, Myc-CaP allografts, and human PC xenografts were treated with AZD1208 (n = 5-11 per group). Androgen-sensitive and castrate-resistant prostate cancer (CRPC) models were studied as well as the effects of hypoxia and radiation. RNA sequencing was used to analyze drug-induced gene expression changes. Results were analyzed with χ2 test. Student's t test and nonparametric Mann-Whitney rank sum U Test. All statistical tests were two-sided. Results: AZD1208 inhibited tumorigenesis in tissue recombinants, Myc-CaP, and human PC xenograft models. PIM inhibition decreased c-MYC/Pim1 graft growth by 54.3±39% (P <. 001), decreased cellular proliferation by 46±14% (P =. 016), and increased apoptosis by 326±170% (P =. 039). AZD1208 suppressed multiple protumorigenic pathways, including the MYC gene program. However, it also downregulated the p53 pathway. Hypoxia and radiation induced PIM1 in prostate cancer cells, and AZD1208 functioned as a radiation sensitizer. Recurrent tumors postcastration responded transiently to either AZD1208 or radiation treatment, and combination treatment resulted in more sustained inhibition of tumor growth. Cell lines established from recurrent, AZD1208-resistant tumors again revealed downregulation of the p53 pathway. Irradiated AZD1208-treated tumors robustly upregulated p53, providing a possible mechanistic explanation for the effectiveness of combination therapy. Finally, an AZD1208-resistant gene signature was found to be associated with biochemical recurrence in PC patients. Conclusions: PIM inhibition is a potential treatment for MYC-driven prostate cancers including CRPC, and its effectiveness may be enhanced by activators of the p53 pathway, such as radiation.
UR - http://www.scopus.com/inward/record.url?scp=84925545131&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84925545131&partnerID=8YFLogxK
U2 - 10.1093/jnci/dju407
DO - 10.1093/jnci/dju407
M3 - Article
C2 - 25505253
AN - SCOPUS:84925545131
VL - 107
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
SN - 0027-8874
IS - 2
M1 - dju407
ER -