title: PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene.
abstract: Postchemotherapy relapse presents a major unmet medical need in acute myeloid leukemia (AML), where treatment options are limited. CD25 is a leukemic stem cell marker and a conspicuous prognostic marker for overall/relapse-free survival in AML. Rare occurrence of genetic alterations among PIM family members imposes a substantial hurdle in formulating a compelling patient stratification strategy for the clinical development of selective PIM inhibitors in cancer. Here we show that CD25, a bona fide STAT5 regulated gene, is a mechanistically relevant predictive biomarker for sensitivity to PIM kinase inhibitors. Alone or in combination with tyrosine kinase inhibitors, PIM inhibitors can suppress STAT5 activation and significantly shorten the half-life of MYC to achieve substantial growth inhibition of high CD25-expressing AML cells. Our results highlight the importance of STAT5 and MYC in rendering cancer cells sensitive to PIM inhibitors. Because the presence of a CD25-positive subpopulation in leukemic blasts correlates with poor overall or relapse-free survival, our data suggest that a combination of PIM inhibitors with chemotherapy and tyrosine kinase inhibitors could improve long-term therapeutic outcomes in CD25-positive AML.
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Zhuyan
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Anlai
authors.initials: A
authors.lastname: Wang
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Mikhail
authors.initials: M
authors.lastname: Levit
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Sanofi, Lead Generation and Candidate Realization, Waltham, MA; and.
authors.forename: Claude
authors.initials: C
authors.lastname: Barberis
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Vitry-Sur-Seine, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Tabart
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Jingxin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Dietmar
authors.initials: D
authors.lastname: Hoffmann
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Dmitri
authors.initials: D
authors.lastname: Wiederschain
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rocnik
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Fangxian
authors.initials: F
authors.lastname: Sun
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Josh
authors.initials: J
authors.lastname: Murtie
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Christoph
authors.initials: C
authors.lastname: Lengauer
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Stefan
authors.initials: S
authors.lastname: Gross
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Bailin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Sanofi, Lead Generation and Candidate Realization, Waltham, MA; and.
authors.forename: Vinod
authors.initials: V
authors.lastname: Patel
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Vitry-Sur-Seine, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Schio
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Francisco
authors.initials: F
authors.lastname: Adrian
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Marion
authors.initials: M
authors.lastname: Dorsch
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Vitry-Sur-Seine, France.
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Echeverria
authors.affiliation: Sanofi Oncology, Discovery and Early Development, Cambridge, MA;
authors.forename: Shih-Min A
authors.initials: SM
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001752:Blast Crisis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D059748:Proteolysis / Q000187:drug effects*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D050799:STAT5 Transcription Factor; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1