PIM kinase inhibitors block the growth of primary T-cell acute lymphoblastic leukemia: Resistance pathways identified by network modeling analysis

James T. Lim, Neha Singh, Libia A. Leuvano, Valerie S. Calvert, Emanuel F. Petricoin, David T. Teachey, Richard B. Lock, Megha Padi, Andrew S. Kraft, Sathish K.R. Padi

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Despite significant progress in understanding the genetic landscape of T-cell acute lymphoblastic leukemia (T-ALL), the discovery of novel therapeutic targets has been difficult. Our results demonstrate that the levels of PIM1 protein kinase is elevated in early T-cell precursor ALL (ETP-ALL) but not in mature T-ALL primary samples. Small-molecule PIM inhibitor (PIMi) treatment decreases leukemia burden in ETP-ALL. However, treatment of animals carrying ETP-ALL with PIMi was not curative. To model other pathways that could be targeted to complement PIMi activity, HSB-2 cells, previously characterized as a PIMi-sensitive T-ALL cell line, were grown in increasing doses of PIMi. Gene set enrichment analysis of RNA sequencing data and functional enrichment of network modules demonstrated that the HOXA9, mTOR, MYC, NFkB, and PI3K-AKT pathways were activated in HSB-2 cells after long-term PIM inhibition. Reverse phase protein array–based pathway activation mapping demonstrated alterations in the mTOR, PI3K-AKT, and NFkB pathways, as well. PIMi-tolerant HSB-2 cells contained phosphorylated RelA-S536 consistent with activation of the NFkB pathway. The combination of NFkB and PIMis markedly reduced the proliferation in PIMi-resistant leukemic cells showing that this pathway plays an important role in driving the growth of T-ALL. Together these results demonstrate key pathways that are activated when HSB-2 cell line develop resistance to PIMi and suggest pathways that can be rationally targeted in combination with PIM kinases to inhibit T-ALL growth.

Original languageEnglish (US)
Pages (from-to)1809-1821
Number of pages13
JournalMolecular Cancer Therapeutics
Volume19
Issue number9
DOIs
StatePublished - Sep 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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