Synergism of FAK and tyrosine kinase inhibition in Ph+ B-ALL

Churchman, Michelle L.; Evans, Kathryn; Richmond, Jennifer; Robbins, Alissa K.; Jones, Luke; Shapiro, Irina M.; Pachter, Jonathan A.; Weaver, David T.; Houghton, Peter J.; Smith, Malcolm A.; Lock, Richard B.; Mullighan, Charles G.

doi:10.1172/jci.insight.86082

Cited by 48 publications

(47 citation statements)

References 38 publications

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“…FAK is a key effector of integrin signaling that is repressed by IKAROS in large pre-B cells (Joshi et al 2014). A combination therapy with inhibitors for the ABL and FAK shows promise in reducing adhesion properties and leukemia-initiating frequencies in human B-ALL (Churchman et al 2016). Thus, previously established protocols combined with recent insights into the IKAROS-based signaling and transcriptional networks in pre-B cells can provide more effective approaches to target high-risk B-ALL.…”

Section: Ikaros and Polycomb Repression Of A B-cell-epithelial Transimentioning

confidence: 99%

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

Georgopoulos

2017

Genes Dev.

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Lymphocyte differentiation is set to produce myriad immune effector cells with the ability to respond to multitudinous foreign substances. The uniqueness of this developmental system lies in not only the great diversity of cellular functions that it can generate but also the ability of its differentiation intermediates and mature effector cells to expand upon demand, thereby providing lifelong immunity. Surprisingly, the goals of this developmental system are met by a relatively small group of DNA-binding transcription factors that work in concert to control the timing and magnitude of gene expression and fulfill the demands for cellular specialization, expansion, and maintenance. The cellular and molecular mechanisms through which these lineage-promoting transcription factors operate have been a focus of basic research in immunology. The mechanisms of development discerned in this effort are guiding clinical research on disorders with an immune cell base. Here, I focus on IKAROS, one of the earliest regulators of lymphoid lineage identity and a guardian of lymphocyte homeostasis.

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Section: Ikaros and Polycomb Repression Of A B-cell-epithelial Transimentioning

confidence: 99%

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

Georgopoulos

2017

Genes Dev.

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“…We and others have shown that the focal adhesion kinase (FAK) pathway is activated downstream of integrin signaling, and is activated in Ikaros-mutated BCR-ABL1 ALL (42, 54, 55). FAK serves to integrate a variety of cell surface signaling inputs, leading to downstream activation of gene expression and reorganization of cytoskeletal architecture.…”

Section: Targeting Adhesion Molecule Signaling In Ikaros Mutant All: mentioning

confidence: 99%

“…We systematically examined activation of FAK signaling pathways and the potential of FAK inhibition in a series of mouse and human cell models (54). Using phosphoproteomic analysis, we showed increased phosphorylation of FAK1, also known as Protein Tyrosine Kinase 2 (PTK2), and FAK2 (PTK2b) in Ikaros mutant tumors, and activation of FAK signaling as shown by elevated levels of p130Cas, a downstream target of FAK.…”

Section: Targeting Adhesion Molecule Signaling In Ikaros Mutant All: mentioning

confidence: 99%

“…As observed with bexarotene, this agent potently reversed the leukemic cell mislocalization characteristic of Ikaros-mutant leukemia. FAK inhibition was also effective in reversing adherence and inducing cell cycle arrest in other IKZF1- mutated cells such as Ph-like ALL cells harboring other fusions of ABL1 or other cytokine receptor alterations such as EPOR (54). …”

Section: Targeting Adhesion Molecule Signaling In Ikaros Mutant All: mentioning

confidence: 99%

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Ikaros: Exploiting and targeting the hematopoietic stem cell niche in B-progenitor acute lymphoblastic leukemia

Churchman

Mullighan

2017

Experimental Hematology

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Genetic alterations of IKZF1 encoding the lymphoid transcription factor IKAROS are a hallmark of high risk B-progenitor ALL such as BCR-ABL1 positive (Ph+) and Ph-like ALL, and are associated with poor outcome, even in the era of contemporary chemotherapy incorporating tyrosine kinase inhibitors in the treatment of Ph+ ALL. Recent experimental mouse modeling of B-progenitor ALL has shown that IKZF1 alterations have multiple effects, including arresting differentiating, skewing lineage of leukemia from myeloid to lymphoid, and in Ph+ leukemia, conferring resistance to TKI therapy without abrogating ABL1 inhibition. These effects are in part mediated by acquisition of an aberrant hematopoietic stem cell like program accompanied by induction of cell surface expression of stem cell and adhesion molecules that mediate extravascular invasion and residence in the niche, and activation of integrin signaling pathways. These effects can be exploited therapeutically using several approaches. IKZF1 alterations also result in upregulation of RXRA that encodes part of the heterodimeric retinoic acid X receptor. Rexinoids, a synthetic class of retinoids that specifically bind to retinoid “X” receptors, such as bexarotene potently reverse aberrant adhesion and niche mislocalization in vivo, and induce differentiation and cell cycle arrest. Focal adhesion kinase inhibitors block the downstream integrin-mediated signaling, and also reverse adhesion and niche mislocalization. Both agents act synergistically with TKI to prolong survival of Ph+ ALL in mouse and human xenograft model, with long term remission induced by FAK inhibitors. Thus, these findings provide important new conceptual insights into the mechanisms by which IKZF1 alterations result in drug resistance, and indicate that therapeutic strategies directed against the pathways deregulated by mutation, rather than attempting to restore IKZF1 expression directly, represent promising therapeutic approaches in this disease.

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“…A recent study in a patient-derived xenograft model of mesothelioma showed that FAK inhibitor VS-4718 preferentially eliminated the cancer stem cells that were enriched following treatment with chemotherapeutic agents (11). VS-4718 treatment in combination with dasatinib prolonged survival in a model of B-ALL (12). Several FAK inhibitors, such as VS-4718, have entered clinical trials (NCT01849744, NCT02651727) in solid tumors.…”

Section: Introductionmentioning

confidence: 99%

Focal Adhesion Kinase as a Potential Target in AML and MDS

Carter

Mak

Wang

et al. 2017

Molecular Cancer Therapeutics

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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 with FLT3-ITD (P = 0.0024) or RAS (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 to normal CD34+ cells. MDS patients with higher FAK in CD34+ cells tended to have better OS (P = 0.05). FAK expression was significantly higher in MDS patients who later transformed to compared with not transformed to AML and in AML patients who transformed from MDS compared with those with de novo AML. Co-culture with mesenchymal stromal cells (MSCs) 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.

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Synergism of FAK and tyrosine kinase inhibition in Ph+ B-ALL

Cited by 48 publications

References 38 publications

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

Ikaros: Exploiting and targeting the hematopoietic stem cell niche in B-progenitor acute lymphoblastic leukemia

Focal Adhesion Kinase as a Potential Target in AML and MDS

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