2. Academic Validation
  3. The eIF2-alpha kinase HRI is a novel therapeutic target in multiple myeloma

The eIF2-alpha kinase HRI is a novel therapeutic target in multiple myeloma

  • Leuk Res. 2017 Apr;55:23-32. doi: 10.1016/j.leukres.2017.01.007.
Nicholas Burwick 1,  Michael Y Zhang 2,  Pilar de la Puente 3,  Abdel Kareem Azab 3,  Teresa S Hyun 4,  Melisa Ruiz-Gutierrez 5,  Marilyn Sanchez-Bonilla 2,  Tomoka Nakamura 2,  Jeffrey J Delrow 6,  Vivian L MacKay 7,  Akiko Shimamura 8
Affiliations

Affiliations

  • 1 Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA; Department of Medicine, University of Washington Medical Center, 1705 NE Pacific St., Seattle, WA, USA. Electronic address: nburwick@u.washington.edu.
  • 2 Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA.
  • 3 Department of Radiation Oncology, Cancer Biology Division, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
  • 4 Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA; Department of Pathology, University of Washington Medical Center, 1705 NE Pacific St., Seattle, WA, USA.
  • 5 Department of Pediatric Hematology/Oncology, Seattle Children's Hospital, 4800 Sand Point Way, Seattle, WA, USA; Department of Pediatrics, University of Washington, 1959 NE Pacific St., Seattle, WA, USA.
  • 6 Genomics Resource, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA.
  • 7 Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • 8 Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA; Department of Pediatric Hematology/Oncology, Seattle Children's Hospital, 4800 Sand Point Way, Seattle, WA, USA; Department of Pediatrics, University of Washington, 1959 NE Pacific St., Seattle, WA, USA.
PMID: 28119225 DOI: 10.1016/j.leukres.2017.01.007
Abstract

Dexamethasone (dex) induces Apoptosis in multiple myeloma (MM) cells and is a frontline treatment for this disease. However resistance to dex remains a major challenge and novel treatment approaches are needed. We hypothesized that dex utilizes translational pathways to promote Apoptosis in MM and that specific targeting of these pathways could overcome dex-resistance. Global unbiased profiling of mRNA translational profiles in MM cells treated with or without dex revealed that dex significantly repressed eIF2 signaling, an important pathway for regulating ternary complex formation and protein synthesis. We demonstrate that dex induces the phosphorylation of eIF2α resulting in the translational upregulation of ATF4, a known eIF2 regulated mRNA. Pharmacologic induction of eIF2α phosphorylation via activation of the heme-regulated eIF2α kinase (HRI) induced Apoptosis in MM cell lines and in primary MM cells from patients with dex-resistant disease. In addition, co-culture with marrow stroma failed to protect MM cells from Apoptosis induced by targeting the eIF2 pathway. Combination therapy with rapamycin, an mTOR Inhibitor, and BTdCPU, an activator of HRI, demonstrated additive effects on Apoptosis in dex-resistant cells. Thus, specific activation of the eIF2α kinase HRI is a novel therapeutic target in MM that can augment current treatment strategies.

Keywords

Apoptosis; Dexamethasone; Multiple myeloma; eIF2 signaling.

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