Chimeric kinase ALK induces expression of NAMPT and selectively depends on this metabolic enzyme to sustain its own oncogenic function

Qian Zhang, Johnvesly Basappa, Hong Y. Wang, Selene Nunez-Cruz, Cosimo Lobello, Shengchun Wang, Xiaobin Liu, Seble Chekol, Lili Guo, Amy Ziober, Reza Nejati, Alex Shestov, Michael Feldman, Jerry D. Glickson, Suzanne D. Turner, Ian A. Blair, Chi Van Dang, Mariusz A. Wasik

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

As we show in this study, NAMPT, the key rate-limiting enzyme in the salvage pathway, one of the three known pathways involved in NAD synthesis, is selectively over-expressed in anaplastic T-cell lymphoma carrying oncogenic kinase NPM1::ALK (ALK + ALCL). NPM1::ALK induces expression of the NAMPT-encoding gene with STAT3 acting as transcriptional activator of the gene. Inhibition of NAMPT affects ALK + ALCL cells expression of numerous genes, many from the cell-signaling, metabolic, and apoptotic pathways. NAMPT inhibition also functionally impairs the key metabolic and signaling pathways, strikingly including enzymatic activity and, hence, oncogenic function of NPM1::ALK itself. Consequently, NAMPT inhibition induces cell death in vitro and suppresses ALK + ALCL tumor growth in vivo. These results indicate that NAMPT is a novel therapeutic target in ALK + ALCL and, possibly, other similar malignancies. Targeting metabolic pathways selectively activated by oncogenic kinases to which malignant cells become “addicted” may become a novel therapeutic approach to cancer, alternative or, more likely, complementary to direct inhibition of the kinase enzymatic domain. This potential therapy to simultaneously inhibit and metabolically “starve” oncogenic kinases may not only lead to higher response rates but also delay, or even prevent, development of drug resistance, frequently seen when kinase inhibitors are used as single agents. [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)2436-2447
Number of pages12
JournalLeukemia
Volume37
Issue number12
DOIs
StatePublished - Nov 2023

Keywords

  • Anaplastic Lymphoma Kinase/metabolism
  • Cell Line, Tumor
  • Humans
  • Lymphoma, Large-Cell, Anaplastic/genetics
  • Nuclear Proteins/genetics
  • Receptor Protein-Tyrosine Kinases/metabolism
  • Signal Transduction

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