Targeting Focal Adhesion Kinase Suppresses the Malignant Phenotype in Rhabdomyosarcoma Cells

Waters, Alicia M.; Stafman, Laura L.; Garner, Evan F.; Mruthyunjayappa, Smitha; Stewart, Jerry E.; Mroczek‐Musulman, Elizabeth; Beierle, Elizabeth A.

doi:10.1016/j.tranon.2016.06.001

Cited by 13 publications

(19 citation statements)

References 39 publications

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“…In accordance with this prominent role of FAK, we found that its expression in sarcoma patient samples significantly correlated with tumor grade and aggressiveness. These findings about the role of FAK in invasion and metastasis are in line with previous studies in other sarcoma subtypes [31] , [32] .…”

Section: Discussionsupporting

confidence: 92%

“…Likewise, the expression and activation status of FAK have been related with decreased overall survival and metastasis-free survival and increased migration in osteosarcoma [31] . In addition, FAK inhibition resulted in decreased invasion, migration, and tumor growth in rhabdomyosarcoma [32] . Here, we used our previously developed MRCLS model [33] , [34] , as well as an MRCLS cell line, to thoroughly characterize the mechanisms used by FUS-CHOP to promote cell invasion.…”

Section: Introductionmentioning

confidence: 96%

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FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway

et al. 2018

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Deregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one of the most activated kinases. Here we used a cell-of-origin model of MRCLS and an MRCLS cell line to thoroughly characterize the mechanisms of cell invasion induced by FUS-CHOP using in vitro (3D spheroid invasion assays) and in vivo (chicken chorioallantoic membrane model) approaches. FUS-CHOP expression activated SRC-FAK signaling and increased the invasive ability of MRCLS cells. In addition, FAK expression was found to significantly correlate with tumor aggressiveness in sarcoma patient samples. The involvement of SRC/FAK activation in FUS-CHOP–mediated invasion was further confirmed using the SRC inhibitor dasatinib, the specific FAK inhibitor PF-573228, and FAK siRNA. Notably, dasatinib and PF573228 could also efficiently block the invasion of cancer stem cell subpopulations. Downstream of SRC/FAK signaling, we found that FUS-CHOP expression increases the levels of the RHO/ROCK downstream effector phospho-MLC2 (T18/S19) and that this activation was prevented by dasatinib or PF573228. Moreover, the ROCK inhibitor RKI-1447 was able to completely abolish invasion in FUS-CHOP–expressing cells. These data uncover the involvement of SRC/FAK/RHO/ROCK signaling axis in FUS-CHOP–mediated invasion, thus providing a rationale for testing inhibitors of this pathway as potential novel antimetastatic agents for MRCLS treatment.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 96%

FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway

et al. 2018

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“…With increasing concentrations, these two drugs decreased total FAK expression in both PDXs and these findings have been noted in other cancer types such as pancreatic cancer [40, 41]. Prior pediatric studies utilizing PF and Y15 demonstrated decreased cell viability and proliferation with an increase in apoptotic markers [19, 21, 28, 35, 42]. Our results demonstrated similar findings with significantly decreased cell survival and proliferation with both PF and Y15 in the primary and metastatic PDXs.…”

Section: Discussionsupporting

confidence: 87%

The effects of focal adhesion kinase and platelet-derived growth factor receptor beta inhibition in a patient-derived xenograft model of primary and metastatic Wilms tumor

et al. 2019

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Aggressive therapies for patients with metastatic Wilms tumor (WT) with subsequent severe late effects warrant the search for novel therapies. The role of focal adhesion kinase (FAK), a non-receptor tyrosine kinase important in pediatric solid tumor development and progression, has not been examined in metastatic WT. Using a novel patient-derived xenograft (PDX) of a primary and matched, isogenic, metastatic WT, the hypothesis of the current study was that FAK would contribute to metastatic WT and small molecule inhibition would decrease tumor growth. Immunohistochemical staining, immunoblotting, cell viability and proliferation assays, cell cycle analysis, and cellular motility and attachment-independent growth assays were performed. FAK was present and phosphorylated in both WT PDXs and in the human samples from which they were derived. FAK inhibition decreased cellular survival, proliferation, and cell cycle progression in both PDXs but only significantly decreased migration, invasion, and attachment-independent growth in the primary WT PDX. Kinomic profiling revealed that platelet-derived growth factor receptor beta (PDGFRβ) may be affected by FAK inhibition in WT. Pharmacologic inhibition of FAK and PDGFRβ was synergistic in primary WT PDX cells. These findings broaden the knowledge of metastatic WT and support further investigations on the potential use of FAK and PDGFRβ inhibitors.

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“…Ectopic sarcoma xenograft models were previously established elsewhere by subcutaneous injection of SJCRH30 [ 57 ], SK-UT-1 [ 58 ], MES-SA [ 58 ], MES-SA/Dx5 [ 59 ], A673 [ 60 ] or SYO-1 [ 61 ] cells. Cells were resuspended in Hank's Balanced Salt Solution (Thermo Fisher Scientific, Waltham, MA) and subcutaneously transplanted into the back of nude mice.…”

Section: Methodsmentioning

confidence: 99%

Antitumor profile of the PI3K inhibitor ZSTK474 in human sarcoma cell lines

et al. 2018

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Treatment of patients with advanced sarcoma remains challenging due to lack of effective medicine, with the development of novel drugs being of keen interest. A pan-PI3K inhibitor, ZSTK474, has been evaluated in clinical trials against a range of advanced solid tumors, with clinical benefit shown in sarcoma patients. In the present study, we developed a panel of 14 human sarcoma cell lines and investigated the antitumor effect of 24 anticancer agents including ZSTK474, other PI3K inhibitors, and those clinically used for sarcoma treatment. ZSTK474 exhibited a similar antiproliferative profile to other PI3K inhibitors but was clearly different from the other drugs examined. Indeed, ZSTK474 inhibited PI3K-downstream pathways, in parallel to growth inhibition, in all cell lines examined, showing proof-of-concept of PI3K inhibition. In addition, ZSTK474 induced apoptosis selectively in Ewing's sarcoma (RD-ES and A673), alveolar rhabdomyosarcoma (SJCRH30) and synovial sarcoma (SYO-1, Aska-SS and Yamato-SS) cell lines, all of which harbor chromosomal translocation and resulting oncogenic fusion genes, EWSR1-FLI1, PAX3-FOXO1 and SS18-SSX, respectively. Finally, animal experiments confirmed the antitumor activity of ZSTK474 in vivo, with superior efficacy observed in translocation-positive cells. These results suggest that ZSTK474 could be a promising drug candidate for treating sarcomas, especially those harboring chromosomal translocation.

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Targeting Focal Adhesion Kinase Suppresses the Malignant Phenotype in Rhabdomyosarcoma Cells

Cited by 13 publications

References 39 publications

FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway

FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway

The effects of focal adhesion kinase and platelet-derived growth factor receptor beta inhibition in a patient-derived xenograft model of primary and metastatic Wilms tumor

Antitumor profile of the PI3K inhibitor ZSTK474 in human sarcoma cell lines

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