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Focal Adhesion Kinase as a Potential Target in AML and MDS.
Bing Z Carter1, Po Yee Mak2, Xiangmeng Wang2
1Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. mandreef@mdanderson.org bicarter@mdanderson.org.
Molecular Cancer Therapeutics
|March 9, 2017
Summary
Focal adhesion kinase (FAK) is a potential therapeutic target in myeloid leukemia. High FAK expression correlates with unfavorable outcomes in acute myeloid leukemia (AML) and myeloid dysplastic syndrome (MDS), while FAK inhibition improves survival.
Area of Science:
- Molecular oncology
- Hematologic malignancies
Background:
- Focal adhesion kinase (FAK) is crucial for cell functions in solid tumors.
- FAK's role in myeloid leukemia, including acute myeloid leukemia (AML) and myeloid dysplastic syndrome (MDS), is under-investigated.
- Understanding FAK's expression and function is vital for novel therapeutic strategies in leukemia.
Purpose of the Study:
- To investigate the expression and functional significance of FAK in AML and MDS.
- To explore the correlation of FAK levels with clinical parameters and patient outcomes.
- To evaluate FAK as a potential therapeutic target in myeloid leukemias.
Main Methods:
- Utilized reverse-phase protein arrays (RPPA) on large cohorts of newly diagnosed AML and MDS samples.
- Analyzed FAK protein levels in relation to cytogenetics, mutations (FLT3-ITD, RAS), and cell populations (CD34+, CD34+CD38-).
- Assessed the impact of FAK inhibition on leukemia cell behavior in vitro and in vivo using a xenograft model.
Main Results:
- High FAK expression in AML correlated with unfavorable cytogenetics and increased relapse risk.
- FAK levels were lower in patients with FLT3-ITD or RAS mutations and linked to p-SRC and integrinβ3.
- FAK was significantly elevated in MDS stem cells (CD34+) and associated with better overall survival in MDS patients; higher FAK observed in MDS transforming to AML and in AML transformed from MDS.
- Coculture with mesenchymal stromal cells (MSC) increased FAK in AML cells.
- FAK inhibition reduced MSC-mediated adhesion/migration, enhanced AML cell viability, and prolonged survival in a murine model.
Conclusions:
- FAK plays a significant role in regulating leukemia-stromal interactions and promoting leukemia cell survival.
- FAK expression patterns are associated with specific genetic mutations and clinical outcomes in AML and MDS.
- FAK represents a promising therapeutic target for myeloid leukemias, particularly in contexts involving stromal interactions.
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