Tailored therapeutic strategies for synovial sarcoma: Receptor tyrosine kinase pathway analyses predict sensitivity to the mTOR inhibitor RAD001

Yasui, Hirohiko; Naka, Norifumi; Imura, Yoshinori; Outani, Hidetatsu; Kaneko, Keiko; Hamada, Kenichiro; Sasagawa, Satoru; Araki, Nobuhito; Ueda, Takafumi; Itoh, Kazuyuki; Myoui, Akira; Yoshikawa, Hideki

doi:10.1016/j.canlet.2014.01.027

Cited by 13 publications

(17 citation statements)

References 29 publications

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“…Moreover, additional inhibitors of mTOR that have similar target profiles, such as CCI-779, RAD001, and AP23573, have been developed (226). Combined treatment with RAD001 and the PDGFRa inhibitor pazopanib showed an antitumor effect in xenograft models in synovial sarcoma cells (227). Additionally, a recent clinical trial testing the target effects and safety profile of RAD001 was performed in patients diagnosed with NSCLC.…”

Section: Clinical Relevance Of Targeting Pdgf Signaling In Human Disementioning

confidence: 97%

Platelet-Derived Growth Factor Signaling in the Lung. From Lung Development and Disease to Clinical Studies

Noskovičová

Petřek²,

Eickelberg³

et al. 2015

Am J Respir Cell Mol Biol

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Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) represent one of the most intensively studied families of growth factors in the last four decades. PDGF signaling plays an essential role in cell proliferation, differentiation, migration, and survival. In vivo studies have documented an important role of PDGF signaling in the normal development of several organs, such as the kidney, eye, or lung. PDGF signaling is essential for the formation of intact mesenchymal cells during embryogenesis. Recently, this knowledge has been extended to a role of PDGF signaling in diseases in general, such as cancer and atherosclerosis, and more importantly in lung diseases, including pulmonary arterial hypertension, lung cancer, and lung fibrosis. In this review, we provide an up-to-date overview of PDGF signaling, including tissue- and cell-type-specific expression patterns and effects. We highlight current therapeutic approaches modifying PDGF signaling in lung diseases and summarize clinical trials in which PDGF signaling has been inhibited. In conclusion, although PDGF inhibition has been used in multiple clinical trials, we suggest that more elaborate and specific approaches for spatio-temporal control of PDGF signaling are required for developing personalized approaches involving PDGF signaling in lung disease.

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Section: Clinical Relevance Of Targeting Pdgf Signaling In Human Disementioning

confidence: 97%

Platelet-Derived Growth Factor Signaling in the Lung. From Lung Development and Disease to Clinical Studies

Noskovičová

Petřek²,

Eickelberg³

et al. 2015

Am J Respir Cell Mol Biol

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“…Therefore it is critical that experimental findings attributed to synovial sarcoma biology from experimental systems are verified in models derived from primary human tumor tissue expressing SS18-SSX under its endogenous promoter. These include several published cell lines grown as monolayers, 3D spheroids (42) or as xenografts (43). Results ultimately will have to be verified on patient tissue samples.…”

Section: The Cellular Background For Ss18-ssx Oncogenesismentioning

confidence: 99%

“…These interactions underlie intrinsic resistance to PI3K/AKT/mTORC1 targeted monotherapies in synovial sarcoma, for example involving feedback activation of AKT following MTOR inhibition, which can be mediated by both IFG1R and PDGFRA (43, 52). These data support the combination of mTOR inhibitors with inhibitors of particular RTKs that potentiate feedback AKT activation in a given tumor.…”

Section: Targetable Oncogenic Pathways Active In Synovial Sarcomamentioning

confidence: 99%

Synovial Sarcoma: Recent Discoveries as a Roadmap to New Avenues for Therapy

2015

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Oncogenesis in synovial sarcoma is driven by the chromosomal translocation t(X,18; p11,q11), which generates an in-frame fusion of the SWI/SNF subunit SS18 to the C-terminal repression domains of SSX1 or SSX2. Proteomic studies have identified an integral role of SS18-SSX in the SWI/SNF complex, and provide new evidence for mistargeting of polycomb-repression in synovial sarcoma. Two recent in vivo studies are highlighted, providing additional support for the importance of Wnt signaling in synovial sarcoma: one uses a conditional mouse model where knockout of beta-catenin prevents tumor formation, and another uses a small molecule inhibitor of beta-catenin in xenograft models.

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“…These cancers range from genetically simple tumours originating from single driver events such as the SS18-SSX fusion in synovial sarcomas to cancers that harbour more complex karyotypes such as head and neck cancers (15, 16). Compelling data from many studies show that cancers are likely to have evolved RTK co-activation as a generic means for driving tumour growth and providing a buffering system to limit the lethal effects of microenvironmental insults including therapy.…”

Section: General Principles Of Rtk Co-activationmentioning

confidence: 99%

“…Interestingly, emerging data from functional screens and phosphoproteomic studies show that co-activation may also be induced by alterations in non-kinases including proteins that are widely considered to be “undruggable”, such as phosphatases, chromatin remodelling complexes and transcription factors (4, 16, 30, 31). One example is the protein tyrosine phosphatase PTPN12 which is deleted in 22% of breast cancers and 13% of lung cancers and found to be a tumour suppressor in a mouse model of breast cancer (30, 32).…”

Section: General Principles Of Rtk Co-activationmentioning

confidence: 99%

Exploiting receptor tyrosine kinase co-activation for cancer therapy

Tan

Vyse

Huang

2017

Drug Discovery Today

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Studies over the past decade have shown that Receptor Tyrosine Kinase (RTK) co-activation is prevalent in many cancer types. Compelling data demonstrates that cancers are likely to have evolved RTK co-activation as a generic means for driving tumour growth and providing a buffering system to limit the lethal effects of microenvironmental insults including therapy. In this review, we summarise the general principles of RTK co-activation gleaned from key studies over the last decade. We discuss direct and indirect approaches to exploit RTK co-activation for cancer therapy and describe recent developments in computational approaches to predict kinase co-dependencies by integrating drug screening data and kinase inhibitor selectivity profiles. We offer a perspective on the outstanding questions in the field focusing on the implications of RTK co-activation on tumour heterogeneity and cancer evolution and conclude by surveying emerging computational and experimental approaches that will provide further insights into the biology of RTK co-activation and deliver new developments in effective cancer therapies.

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Tailored therapeutic strategies for synovial sarcoma: Receptor tyrosine kinase pathway analyses predict sensitivity to the mTOR inhibitor RAD001

Cited by 13 publications

References 29 publications

Platelet-Derived Growth Factor Signaling in the Lung. From Lung Development and Disease to Clinical Studies

Platelet-Derived Growth Factor Signaling in the Lung. From Lung Development and Disease to Clinical Studies

Synovial Sarcoma: Recent Discoveries as a Roadmap to New Avenues for Therapy

Exploiting receptor tyrosine kinase co-activation for cancer therapy

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