Ponatinib promotes a G1 cell-cycle arrest of merlin/NF2-deficient human schwann cells

Petrilli, Alejandra M.; García, J.A.S.; Bott, Marga; Plati, Stephani Klingeman; Dinh, Christine T.; Bracho, Olena; Yan, Denise; Zou, Bing; Mittal, Rahul; Telischi, Fred F.; Liu, Xue Zhong; Chang, Long Sheng; Welling, D. Bradley; Copik, Alicja J.; Fernández‐Valle, Cristina

doi:10.18632/oncotarget.15912

Cited by 28 publications

(25 citation statements)

References 64 publications

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“…Earlier studies have shown activation of Src in NF2 wild-type vs NF2 deficient Schwann cell lines 38 and treatment of merlin-deficient mouse Schwann cell lines also identified dasatinib as a potentially effective agent based on the results of a high-throughput drug screen 39 however, this study focused on a more specific Src inhibitor, saracatinib, in combination with the c-Met inhibitor cabozantinib 39 . Dasatinib is FDA-approved for treatment of acute lymphocytic leukemia and chronic myeloid leukemia with mutant Abl kinase expression, and is shown to inhibit oncogenic and invasive processes in blood cancers and solid tumors 40 .…”

Section: Discussionmentioning

confidence: 99%

Combination therapy with mTOR kinase inhibitor and dasatinib as a novel therapeutic strategy for vestibular schwannoma

Sagers

Beauchamp

Zhang

et al. 2020

Sci Rep

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Neurofibromatosis type 2 (NF2) is an inherited disorder characterized by bilateral vestibular schwannomas (VS) that arise from neoplastic Schwann cells (SCs). NF2-associated VSs are often accompanied by meningioma (MN), and the majority of NF2 patients show loss of the NF2 tumor suppressor. mTORC1 and mTORC2-specific serum/glucocorticoid-regulated kinase 1 (SGK1) are constitutively activated in Mn with loss of NF2. In a recent high-throughput kinome screen in NF2-null human arachnoidal and meningioma cells, we showed activation of EPH RTKs, c-KIT, and SFK members independent of mTORC1/2 activation. Subsequently, we demonstrated in vitro and in vivo efficacy of combination therapy with the dual mTORC1/2 inhibitor AZD2014 and the multi-kinase inhibitor dasatinib. For these reasons, we investigated activated mTORC1/2 and EPH receptor-mediated signaling in sporadic and NF2-associated VS. Using primary human VS cells and a mouse allograft model of schwannoma, we evaluated the dual mTORC1/2 inhibitor AZD2014 and the tyrosine kinase inhibitor dasatinib as monotherapies and in combination. Escalating dose-response experiments on primary VS cells grown from 15 human tumors show that combination therapy with AZD2014 and dasatinib is more effective at reducing metabolic activity than either drug alone and exhibits a therapeutic effect at a physiologically reasonable concentration (~0.1 µM). In vivo, while AZD2014 and dasatinib each inhibit tumor growth alone, the effect of combination therapy exceeds that of either drug. Co-targeting the mTOR and EPH receptor pathways with these or similar compounds may constitute a novel therapeutic strategy for VS, a condition for which there is no FDA-approved pharmacotherapy. Vestibular schwannoma (VS) is the most common tumor of the cerebellopontine angle and the fourth most common intracranial tumor in humans. VSs are formed from neoplastic Schwann cells of the vestibular nerve and can arise sporadically or as part of a debilitating tumor syndrome known as neurofibromatosis type 2 (NF2) that can include multiple schwannomas, meningiomas, and ependymomas 1. The majority of VS patients generally report sensorineural hearing loss and tinnitus, with others experiencing dizziness, loss of balance, or facial

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Section: Discussionmentioning

confidence: 99%

Combination therapy with mTOR kinase inhibitor and dasatinib as a novel therapeutic strategy for vestibular schwannoma

Sagers

Beauchamp

Zhang

et al. 2020

Sci Rep

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“…This result suggests that ponatinib would have been a much more potent inhibitor for HCC cells had it not activated the PDK1/Akt/mTOR pathway. There are conflicting reports on if ponatinib inhibits [20,44,45] or activates [41] Akt signaling in the literature. The discrepancy suggests that the effects of ponatinib on Akt signaling may be dependent on cell signaling background.…”

Section: Discussionmentioning

confidence: 99%

“…Ponatinib (AP24534), an orally available and potent multi-targeted kinase inhibitor, has been approved by the Food and Drug Administration (FDA) to treat imatinib-resistant patients with chronic myelogenous leukemia [17,18]. Ponatinib inhibits both native and mutant forms of BCR-ABL, including the T315I gatekeeper mutant that is resistant to other tyrosine-kinase inhibitors (TKIs) [19,20]. Besides its activity against BCR-ABL, ponatinib also inhibits approximately 50 other PTKs with IC 50 values below 100 nM, including many kinases in the PDGFR, Src, VEGFR, Eph receptor (EphR), and FGFR families [20,21].…”

Section: Introductionmentioning

confidence: 99%

“…Ponatinib inhibits both native and mutant forms of BCR-ABL, including the T315I gatekeeper mutant that is resistant to other tyrosine-kinase inhibitors (TKIs) [19,20]. Besides its activity against BCR-ABL, ponatinib also inhibits approximately 50 other PTKs with IC 50 values below 100 nM, including many kinases in the PDGFR, Src, VEGFR, Eph receptor (EphR), and FGFR families [20,21]. In a panel of 14 cell lines, including breast, lung, and colon cancer cell lines, ponatinib inhibited FGFR-mediated signaling and cell growth significantly in a variety of cell lines [22].…”

Section: Introductionmentioning

confidence: 99%

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Ponatinib Inhibits Proliferation and Induces Apoptosis of Liver Cancer Cells, but Its Efficacy Is Compromised by Its Activation on PDK1/Akt/mTOR Signaling

Liu

Wang

et al. 2019

Molecules

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Ponatinib is a multi-target protein tyrosine kinase inhibitor, and its effects on hepatocellular carcinoma cells have not been previously explored. In the present study, we investigated its effects on hepatocellular carcinoma cell growth and the underlying mechanisms. Toward SK-Hep-1 and SNU-423 cells, ponatinib induces apoptosis by upregulation of cleaved caspase-3 and -7 and promotes cell cycle arrest in the G1 phase by inhibiting CDK4/6/CyclinD1 complex and phosphorylation of retinoblastoma protein. It inhibits the growth-stimulating mitogen-activated protein (MAP) kinase pathway, the phosphorylation of Src on both negative and positive regulation sites, and Jak2 and Stat3 phosphorylation. Surprisingly, it also activates the PDK1, the protein kinase B (Akt), and the mechanistic target of rapamycin (mTOR) signaling pathway. Blocking mTOR signaling strongly sensitizes cells to inhibition by ponatinib and makes ponatinib a much more potent inhibitor of hepatocellular carcinoma cell proliferation. These findings demonstrate that ponatinib exerts both positive and negative effects on hepatocellular cell proliferation, and eliminating its growth-stimulating effects by drug combination or potentially by chemical medication can significantly improve its efficacy as an anti-cancer drug.

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“…Petrilli and colleagues reported that ponatinib is a potential therapeutic compound for the treatment of neurofibromatosis type 2 (NF2) [ 72 ], which is a genetic disorder causing multiple benign tumours in the central and peripheral nervous systems, including vestibular schwannomas. NF2 is caused by mutations in the NF2 gene encoding the tumour suppressor protein merlin (or schwannomin), which regulates many kinase pathways.…”

Section: Solid Tumoursmentioning

confidence: 99%

Recent Studies on Ponatinib in Cancers Other Than Chronic Myeloid Leukemia

Musumeci

Greco

Grossi

et al. 2018

Cancers

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Ponatinib is a third line drug for the treatment of chronic myeloid leukemia patients, especially those that develop the gatekeeper mutation T315I, which is resistant to the first and the second line drugs imatinib, nilotinib, dasatinib and bosutinib. The compound was first identified as a pan Bcr-Abl and Src kinase inhibitor. Further studies have indicated that it is a multitargeted inhibitor that is active on FGFRs, RET, AKT, ERK1/2, KIT, MEKK2 and other kinases. For this reason, the compound has been evaluated on several cancers in which these kinases play important roles, including thyroid, breast, ovary and lung cancer, neuroblastoma, rhabdoid tumours and in myeloproliferative disorders. Ponatinib is also being tested in clinical trials to evaluate its activity in FLT3-ITD acute myelogenous leukemia, head and neck cancers, certain type of lung cancer, gastrointestinal stromal tumours and other malignancies. In this review we report the most recent preclinical and clinical studies on ponatinib in cancers other than CML, with the aim of giving a complete overview of this interesting compound.

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Ponatinib promotes a G1 cell-cycle arrest of merlin/NF2-deficient human schwann cells

Cited by 28 publications

References 64 publications

Combination therapy with mTOR kinase inhibitor and dasatinib as a novel therapeutic strategy for vestibular schwannoma

Combination therapy with mTOR kinase inhibitor and dasatinib as a novel therapeutic strategy for vestibular schwannoma

Ponatinib Inhibits Proliferation and Induces Apoptosis of Liver Cancer Cells, but Its Efficacy Is Compromised by Its Activation on PDK1/Akt/mTOR Signaling

Recent Studies on Ponatinib in Cancers Other Than Chronic Myeloid Leukemia

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