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Targeting Ras signaling in AML: RALB is a small GTPase with big potential.

Authors
  • Pomeroy, Emily J1
  • Eckfeldt, Craig E1, 2
  • 1 Department of Medicine, Division of Hematology, Oncology, & Transplantation, University of Minnesota, Minneapolis, MN, USA.
  • 2 Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Type
Published Article
Journal
Small GTPases
Publication Date
Jan 01, 2020
Volume
11
Issue
1
Pages
39–44
Identifiers
DOI: 10.1080/21541248.2017.1339765
PMID: 28682649
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Acute myeloid leukemia (AML) is a devastating malignancy for which novel treatment approaches are desperately needed. Ras signaling is an attractive therapeutic target for AML because a large proportion of AMLs have mutations in NRAS, KRAS, or genes that activate Ras signaling, and key Ras effectors are activated in virtually all AML patient samples. This has inspired efforts to develop Ras-targeted treatment strategies for AML. Due to the inherent difficulty and disappointing efficacy of targeting Ras proteins directly, many have focused on inhibiting Ras effector pathways. Inhibiting the major oncogenic Ras effectors, the mitogen-activated protein kinase (MAPK) and/or phosphatidylinositiol-3-kinase (PI3K) pathways, has generally demonstrated modest efficacy for AML. While this may be in part related to functional redundancy between these pathways, it is now clear that other Ras effectors have key oncogenic roles. Specifically, the Ras-like (Ral) GTPases have emerged as critical mediators of Ras-driven transformation and AML cell survival. Our group recently uncovered a critical role for RALB signaling in leukemic cell survival and a potential mediator of relapse following Ras-targeted therapy in AML. Furthermore, we found that RALB signaling is hyperactivated in AML patient samples, and inhibiting RALB has potent anti-leukemic activity in preclinical AML models. While key questions remain regarding the importance of RALB signaling across the genetically diverse spectrum of AML, the specific mechanism(s) that promotes leukemic cell survival downstream of RALB, and how to pharmacologically target RALB signaling effectively - RALB has emerged as a critical Ras effector and potential therapeutic target for AML.

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