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

Li, Haoyu; Wang, Yongfeng; Chen, Zhenghu; Lu, Jian; Pan, Jessie; Ye, Yu; Zhao, Yanling; Zhang, Huiyuan; Hu, Tian; Liu, Qing; Yang, Jianhua

doi:10.18632/oncotarget.11580

Cited by 20 publications

(24 citation statements)

References 57 publications

(56 reference statements)

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“…The soft agar assay was performed as previously described4445. Briefly, a 5% (w/v) base agar layer was made by adding agar (214220, Difco Laboratories, Detroit, MI, USA) into distilled water and then autoclavingthe mixture for 50 min before cooling in a 56 °C water bath.…”

Section: Methodsmentioning

confidence: 99%

Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis

Chen

Wang

Yao

et al. 2016

Sci Rep

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Neuroblastoma (NB) is the most common extracranial tumor in children. Unlike in most adult tumors, tumor suppressor protein 53 (p53) mutations occur with a relatively low frequency in NB and the downstream function of p53 is intact in NB cell lines. Wip1 is a negative regulator of p53 and hindrance of Wip1 activity by novel inhibitor GSK2830371 is a potential strategy to activate p53’s tumor suppressing function in NB. Yet, the in vivo efficacy and the possible mechanisms of GSK2830371 in NB have not yet been elucidated. Here we report that novel Wip1 inhibitor GSK2830371 induced Chk2/p53-mediated apoptosis in NB cells in a p53-dependent manner. In addition, GSK2830371 suppressed the colony-formation potential of p53 wild-type NB cell lines. Furthermore, GSK2830371 enhanced doxorubicin- (Dox) and etoposide- (VP-16) induced cytotoxicity in a subset of NB cell lines, including the chemoresistant LA-N-6 cell line. More importantly, GSK2830371 significantly inhibited tumor growth in an orthotopic xenograft NB mouse model by inducing Chk2/p53-mediated apoptosis in vivo. Taken together, this study suggests that GSK2830371 induces Chk2/p53-mediated apoptosis both in vitro and in vivo in a p53 dependent manner.

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Section: Methodsmentioning

confidence: 99%

Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis

Chen

Wang

Yao

et al. 2016

Sci Rep

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“…Recently, it has been suggested that the use of reduced doses of ponatinib (down to 15 mg/day instead of the usual dosage of 45 mg/day) might maintain therapeutic activity in most patients while decreasing the vascular adverse events (24,26). Although clinicians will have to tackle the side effects observed upon ponatinib administration, the results achieved through our study, as well as others (17,18), indicate that this drug has the potential to be employed in clinical trials aimed to evaluate benefits in high-risk NB patients.…”

Section: Discussionmentioning

confidence: 49%

“…Although we could not prove a significant activity of axitinib in our in vivo model, one previous study indicated that axitinib could partially impair the growth of human NB xenografts by inhibiting angiogenesis (16). Notably, independent investigations have very recently proposed ponatinib itself as a drug displaying antitumor efficacy against NB (17,18). Ponatinib proved to inhibit the FGFR1-activated signaling pathway and enhance the cytotoxic effects of doxorubicin on NB cells (18).…”

Section: Discussionmentioning

confidence: 62%

“…Notably, independent investigations have very recently proposed ponatinib itself as a drug displaying antitumor efficacy against NB (17,18). Ponatinib proved to inhibit the FGFR1-activated signaling pathway and enhance the cytotoxic effects of doxorubicin on NB cells (18). Moreover, ponatinib also interferes with the insulin-like growth factor-1 receptor signaling pathways and Src activity, inhibiting cell migration and inducing apoptosis in NB (19).…”

Section: Discussionmentioning

confidence: 99%

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A High-Content Screening of Anticancer Compounds Suggests the Multiple Tyrosine Kinase Inhibitor Ponatinib for Repurposing in Neuroblastoma Therapy

Sidarovich

Mariano

Aveic

et al. 2018

Molecular Cancer Therapeutics

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Novel druggable targets have been discovered in neuroblastoma (NB), paving the way for more effective treatments. However, children with high-risk NB still show high mortality rates prompting for a search of novel therapeutic options. Here, we aimed at repurposing FDA-approved drugs for NB treatment by performing a high-content screening of a 349 anticancer compounds library. In the primary screening, we employed three NB cell lines, grown as three-dimensional (3D) multicellular spheroids, which were treated with 10 μmol/L of the library compounds for 72 hours. The viability of 3D spheroids was evaluated using a high-content imaging approach, resulting in a primary hit list of 193 compounds. We selected 60 FDA-approved molecules and prioritized drugs with multi-target activity, discarding those already in use for NB treatment or enrolled in NB clinical trials. Hence, 20 drugs were further tested for their efficacy in inhibiting NB cell viability, both in two-dimensional and 3D models. Dose-response curves were then supplemented with the data on side effects, therapeutic index, and molecular targets, suggesting two multiple tyrosine kinase inhibitors, ponatinib and axitinib, as promising candidates for repositioning in NB. Indeed, both drugs showed induction of cell-cycle block and apoptosis, as well as inhibition of colony formation. However, only ponatinib consistently affected migration and inhibited invasion of NB cells. Finally, ponatinib also proved effective inhibition of tumor growth in orthotopic NB mice, providing the rationale for its repurposing in NB therapy. .

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“…In this study, we report for the first time that a novel combination of drugs, the BRAF inhibitor PLX4720 and the FDA-approved multitarget TK inhibitor ponatinib, synergistically reduces p-MEK and p-ERK compared with single-drug treatments in BRAF V600E cells. The chemoresistance of ponatinib has been frequently raised as critical issues in the preclinical and clinical settings; this might result in lower effect of ponatinib in vivo compared with in vitro study (31).…”

Section: Discussionmentioning

confidence: 99%

A Combinatorial Strategy for TargetingBRAFV600E-Mutant Cancers with BRAFV600E Inhibitor (PLX4720) and Tyrosine Kinase Inhibitor (Ponatinib)

Ghosh

Kumar²,

Kushchayeva

et al. 2020

Clinical Cancer Research

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◥Purpose: Most aggressive thyroid cancers are commonly associated with a BRAF V600E mutation. Preclinical and clinical data in BRAF V600E cancers suggest that combined BRAF and MEK inhibitor treatment results in a response, but resistance is common. One mechanism of acquired resistance is through persistent activation of tyrosine kinase (TK) signaling by alternate pathways. We hypothesized that combination therapy with BRAF and multitargeting TK inhibitors (MTKI) might be more effective in BRAF V600E thyroid cancer than in single-agent or BRAF and MEK inhibitors.Experimental Design: The combined drug activity was analyzed to predict any synergistic effect using highthroughput screening (HTS) of active drugs. We performed follow-up in vitro and in vivo studies to validate and determine the mechanism of action of synergistic drugs. Results:The MTKI ponatinib and the BRAF inhibitor PLX4720 showed synergistic activity by HTS. This combination significantly inhibited proliferation, colony formation, invasion, and migration in BRAF V600E thyroid cancer cell lines and downregulated pERK/MEK and c-JUN signaling pathways, and increased apoptosis. PLX4720resistant BRAF V600E cells became sensitized to the combination treatment, with decreased proliferation at lower PLX4720 concentrations. In an orthotopic thyroid cancer mouse model, combination therapy significantly reduced tumor growth (P < 0.05), decreased the number of metastases (P < 0.05), and increased survival (P < 0.05) compared with monotherapy and vehicle control.Conclusions: Combination treatment with ponatinib and PLX4720 exhibited significant synergistic anticancer activity in preclinical models of BRAF V600E thyroid cancer, in addition to overcoming PLX4720 resistance. Our results suggest this combination should be tested in clinical trials.

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

Cited by 20 publications

References 57 publications

Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis

Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis

A High-Content Screening of Anticancer Compounds Suggests the Multiple Tyrosine Kinase Inhibitor Ponatinib for Repurposing in Neuroblastoma Therapy

A Combinatorial Strategy for TargetingBRAFV600E-Mutant Cancers with BRAFV600E Inhibitor (PLX4720) and Tyrosine Kinase Inhibitor (Ponatinib)

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