title: Focal Adhesion Kinase as a Potential Target in AML and MDS.
abstract: Although overexpression/activation of focal adhesion kinase (FAK) is widely known in solid tumors to control cell growth, survival, invasion, metastasis, gene expression, and stem cell self-renewal, its expression and function in myeloid leukemia are not well investigated. Using reverse-phase protein arrays in large cohorts of newly diagnosed acute myeloid leukemia (AML) and myeloid dysplastic syndrome (MDS) samples, we found that high FAK expression was associated with unfavorable cytogenetics (P= 2 × 10-4) and relapse (P= 0.02) in AML. FAK expression was significantly lower in patients withFLT3-ITD (P= 0.0024) orRAS(P= 0.05) mutations and strongly correlated with p-SRC and integrinβ3 levels. FAK protein levels were significantly higher in CD34+(P= 5.42 × 10-20) and CD34+CD38-MDS (P= 7.62 × 10-9) cells compared with normal CD34+cells. MDS patients with higher FAK in CD34+cells tended to have better overall survival (P= 0.05). FAK expression was significantly higher in MDS patients who later transformed to compared with those who did not transform to AML and in AML patients who transformed from MDS compared with those withde novoAML. Coculture with mesenchymal stromal cells (MSC) increased FAK expression in AML cells. Inhibition of FAK decreased MSC-mediated adhesion/migration and viability of AML cells and prolonged survival in an AML xenograft murine model. Our results suggest that FAK regulates leukemia-stromal interactions and supports leukemia cell survival; hence, FAK is a potential therapeutic target in myeloid leukemia.Mol Cancer Ther; 16(6); 1133-44. ©2017 AACR.
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. mandreef@mdanderson.org bicarter@mdanderson.org.
authors.forename: Bing Z
authors.initials: BZ
authors.lastname: Carter
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Po Yee
authors.initials: PY
authors.lastname: Mak
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xiangmeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Section of Myelodysplastic Syndromes, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Section of Myelodysplastic Syndromes, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Duncan H
authors.initials: DH
authors.lastname: Mak
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hong
authors.initials: H
authors.lastname: Mu
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vivian R
authors.initials: VR
authors.lastname: Ruvolo
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Kevin
authors.initials: K
authors.lastname: Coombes
authors.affiliation: Life Technologies Corporation, Carlsbad, California.
authors.forename: Nianxiang
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Brittany
authors.initials: B
authors.lastname: Ragon
authors.affiliation: Verastem, Inc., Needham, Massachusetts.
authors.forename: David T
authors.initials: DT
authors.lastname: Weaver
authors.affiliation: Verastem, Inc., Needham, Massachusetts.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Pachter
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Steven
authors.initials: S
authors.lastname: Kornblau
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. mandreef@mdanderson.org bicarter@mdanderson.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D002448:Cell Adhesion; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D051416:Focal Adhesion Protein-Tyrosine Kinases