Inhibition of Mer and Axl receptor tyrosine kinases leads to increased apoptosis and improved chemosensitivity in human neuroblastoma

Li, Yixin; Wang, Xiqian; Bi, Shao‐Jie; Zhao, Kun; Chao, Yu–Faye

doi:10.1016/j.bbrc.2015.01.017

Cited by 23 publications

(14 citation statements)

References 22 publications

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“…Recently, it has been reported that Axl receptor mediates cancer cell resistance to multiple targeted drugs (ALK inhibitor 22 , EGFR inhibitors 23 - 25 , BRAF inhibitor 26 , ERK inhibitor 26 , PI3Kα inhibitor 27 , or antiangiogenic therapy 28 ). Axl also leads to chemoresistance in several cancer types 29 , 30 . Targeting Axl pathway with specific antibody or small molecule inhibitor alone or in combination with other drugs can suppress Axl-mediated signaling pathways and improve therapeutic efficacy 31 .…”

Section: Introductionmentioning

confidence: 99%

Gas6/Axl Axis Contributes to Chemoresistance and Metastasis in Breast Cancer through Akt/GSK-3β/β-catenin Signaling

Wang¹,

Jin²,

Wang³

et al. 2016

Theranostics

128

117

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Chemoresistance in breast cancer has been of great interest in past studies. However, the development of rational therapeutic strategies targeting chemoresistant cells is still a challenge in clinical oncology. By integrating data from global differences of gene expression and phospho-receptor tyrosine kinases between sensitive parental cells (MCF-7) and doxorubicin-resistant cells (MCF-7/ADR), we identified Axl as a potential target for chemoresistance and metastasis in multidrug resistant breast cancer cells. We analyzed Axl expression in 57 breast cancer cell lines and detected a dramatic increase in its expression level in mesenchymal breast cancer cell lines. Axl silencing suppressed invasive and metastatic potentials of chemoresistant breast cancer cells as well as increased elimination of cancer cells when combined with doxorubicin. Furthermore, in preclinical assays, an Axl inhibitor R428 showed increased cell death upon doxorubicin treatment. Additionally, using phospho-kinase array based proteomic analysis, we identified that Akt/GSK-3β/β-catenin cascade was responsible for Axl-induced cell invasion. Nuclear translocation of β-catenin then induced transcriptional upregulation of ZEB1, which in turn regulated DNA damage repair and doxorubicin-resistance in breast cancer cells. Most importantly, Axl was correlated with its downstream targets in tumor samples and was associated with poor prognosis in breast cancer patients. These results demonstrate that Gas6/Axl axis confers aggressiveness in breast cancer and may represent a therapeutic target for chemoresistance and metastasis.

show abstract

Section: Introductionmentioning

confidence: 99%

Gas6/Axl Axis Contributes to Chemoresistance and Metastasis in Breast Cancer through Akt/GSK-3β/β-catenin Signaling

Wang¹,

Jin²,

Wang³

et al. 2016

Theranostics

128

117

View full text Add to dashboard Cite

show abstract

“…Aberrantly activated RTKs have been reported to promote NB tumor progression through activating signaling pathways such as PI3K/AKT/mTOR and JAK/STAT3 [23–26]. Furthermore, inhibition of some RTKs leads to increased apoptosis of NB cells [24]. However, current RTKs inhibitors have limited therapeutic outcomes [27, 28].…”

Section: Introductionmentioning

confidence: 99%

Novel multiple tyrosine kinase inhibitor ponatinib inhibits bFGF-activated signaling in neuroblastoma cells and suppresses neuroblastoma growth in vivo

Wang

Chen

et al. 2016

Oncotarget

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Neuroblastoma (NB) is one of the most common pediatric malignancies in children. Abnormal activation of receptor tyrosine kinases contributes to the pathological development of NB. Therefore, targeting tyrosine kinase receptors to cure NB is a promising strategy. Here, we report that a multi-targeted tyrosine kinase inhibitor ponatinib inhibited NB cell proliferation and induced NB cell apoptosis in a dose-dependent manner. In addition, ponatinib suppressed the colony formation ability of NB cells. Mechanistically, ponatinib effectively inhibited the FGFR1-activated signaling pathway. Ponatinib also enhanced the cytotoxic effects of doxorubicin on NB cells. Furthermore, ponatinib demonstrated anti-tumor efficacy in vivo by inhibiting tumor growth in an orthotopic xenograft NB mouse model. In summary, our results showed that ponatinib inhibited NB growth both in vitro and in vivo.

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“…MerTK overexpression has been detected in high-grade glioblastomas and its knockdown to result in increased sensitivity to etoposide while, conversely, control cells showed elevated MerTK activation upon DNA damage with increase resistance to etoposide (10). Inhibition of Axl and MerTK also led to increased chemosensitivity to temozolomide, carboplatin, and vincristine in astrocytoma (11), and to cisplatin and vincristine in neuroblastoma (12). Axl was also shown to promote resistance to ALK inhibitors in neuroblastoma through induction of epithelialmesenchymal transition (EMT; ref.…”

Section: The Tams As Mediators Of Chemoresistancementioning

confidence: 99%

TAM Receptor Tyrosine Kinases in Cancer Drug Resistance

Vouri

Hafizi

2017

Cancer Research

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Receptor tyrosine kinases (RTK) are major regulators of key biological processes, including cell growth, survival, and differentiation, and were established early on as proto-oncogenes, with aberrant expression linked to tumor progression in many cancers. Therefore, RTKs have emerged as major targets for selective therapy with small-molecule inhibitors. However, despite improvements in survival rates, it is now apparent that the targeting of RTKs with selective inhibitors is only transiently effective, as the majority of patients eventually become resistant to therapy. As chemoresistance is the leading cause of cancer spread, progression, and mortality, there is an increasing need for understanding the mechanisms by which cancer cells can evade therapy-induced cell death. The TAM (Tyro3, Axl, Mer) subfamily of RTKs in particular feature in a variety of cancer types that have developed resistance to a broad range of therapeutic agents, including both targeted as well as conventional chemotherapeutics. This article reviews the roles of TAMs as tumor drivers and as mediators of chemoresistance, and the potential effectiveness of targeting them as part of therapeutic strategies to delay or combat resistance. .

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Inhibition of Mer and Axl receptor tyrosine kinases leads to increased apoptosis and improved chemosensitivity in human neuroblastoma

Cited by 23 publications

References 22 publications

Gas6/Axl Axis Contributes to Chemoresistance and Metastasis in Breast Cancer through Akt/GSK-3β/β-catenin Signaling

Gas6/Axl Axis Contributes to Chemoresistance and Metastasis in Breast Cancer through Akt/GSK-3β/β-catenin Signaling

Novel multiple tyrosine kinase inhibitor ponatinib inhibits bFGF-activated signaling in neuroblastoma cells and suppresses neuroblastoma growth in vivo

TAM Receptor Tyrosine Kinases in Cancer Drug Resistance

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