The next-generation ALK inhibitors

Pall, Georg

doi:10.1097/cco.0000000000000165

Cited by 29 publications

(17 citation statements)

References 27 publications

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“…Following this line of reasoning, the ALK and the MET proto-oncogene, receptor tyrosine kinase (MET) inhibitor Crizotinib is currently being evaluated in combination with radiotherapy and temozolomide [TMZ;the benchmark agent for the management of glioblastoma(Stupp et al, 2005)] in a Phase 1b clinical study in adult patients with newly diagnosed glioblastoma NCT02270034) which may facilitate the development of future studies combining this inhibitor with cannabinoids. A second generation of ALK inhibitors with a lower risk of developing drug resistance in patients, such as Ceritinib or Alectinib, is being already evaluated in clinical studies(Pall, 2015). Alternative approaches to inhibit MDK-ALK axis could also include the use the humanized antibodies against MDK or its receptor ALK.It is worth noting that other growth factors [such as the heparin-bound epidermal growth factor receptor (EGFR) ligand amphiregulin] have been implicated in the resistance to cannabinoid antitumour action(Lorente et al, 2009);(Hart et al, 2004).Thus pharmacological blockade of EGFR, (Lorente et al, 2009) enhances the cell deathpromoting action of THC in cultures of glioma cells.…”

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confidence: 99%

The use of cannabinoids as anticancer agents

Velasco

Hernández-Tiedra

Dávila

et al. 2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

140

101

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It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumor growth in animal models of cancer. Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death. In addition, cannabinoids inhibit tumor angiogenesis and decrease cancer cell migration. The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored. In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area.

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confidence: 99%

The use of cannabinoids as anticancer agents

Velasco

Hernández-Tiedra

Dávila

et al. 2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

140

101

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“…S1B). With respect to the tumor-killing activity of ALK inhibitors (24), we addressed whether AZD3463, LDK378, and AP26113 inhibit STING activation in macrophages through triggering cell death. AZD3463 exhibited cytotoxicity against iBMDMs, pPMs, and RAW264.7 and THP1 cells (fig.…”

Section: Resultsmentioning

confidence: 99%

ALK is a therapeutic target for lethal sepsis

et al. 2017

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Sepsis, a life-threatening organ dysfunction caused by infection, is a major public health concern with limited therapeutic options. We provide evidence to support a role for anaplastic lymphoma kinase (ALK), a tumor-associated receptor tyrosine kinase, in the regulation of innate immunity during lethal sepsis. The genetic disruption of ALK expression diminishes the stimulator of interferon genes (STING)–mediated host immune response to cyclic dinucleotides in monocytes and macrophages. Mechanistically, ALK directly interacts with epidermal growth factor receptor (EGFR) to trigger serine-threonine protein kinase AKT phosphorylation and activate interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) signaling pathways, enabling STING-dependent rigorous inflammatory responses. Moreover, pharmacological or genetic inhibition of the ALK-STING pathway confers protection against lethal endotoxemia and sepsis in mice. The ALK pathway is up-regulated in patients with sepsis. These findings uncover a key role for ALK in modulating the inflammatory signaling pathway and shed light on the development of ALK-targeting therapeutics for lethal systemic inflammatory disorders.

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“…The recent discovery of specific ALK tyrosine kinase inhibitors (TKIs) has dramatically changed the way patients bearing ALK-rearranged tumors are treated 10, 11 . In ALK-rearranged non-small cell lung cancer (NSCLC) crizotinib, as well as next generation ALK TKIs such as ceritinib, alectinib or brigatinib, have proven clinical efficacy 12-14 .…”

Section: Introductionmentioning

confidence: 99%

Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency

et al. 2015

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Most of Anaplastic Large Cell Lymphoma (ALCL) cases carry the t(2;5; p23;q35) that produces the fusion protein NPM-ALK. NPM-ALK deregulated kinase activity drives several pathways that support malignant transformation of lymphoma cells. We found that in ALK-rearranged ALCL cell lines NPM-ALK was distributed in equal amounts between the cytoplasm and the nucleus. Only the cytoplasmic portion was catalytically active in both cell lines and primary ALCL, whereas the nuclear portion was inactive due to heterodimerization with NPM1. Thus, about 50% of the NPM-ALK is not active and sequestered as NPM-ALK/NPM1 heterodimers in the nucleus. Overexpression or re-localization of NPM-ALK to the cytoplasm by NPM genetic knock-out or knock-down caused ERK1/2 increased phosphorylation and cell death through the engagement of an ATM/Chk2 and γH2AX mediated DNA damage response. Remarkably, human NPM-ALK amplified cell lines resistant to ALK tyrosine kinase inhibitors (TKIs) underwent apoptosis upon drug withdrawal as a consequence of ERK1/2 hyperactivation. Altogether, these findings indicate that an excess of NPM-ALK activation and signaling induces apoptosis via oncogenic stress responses. A “drug holiday” where the ALK TKI treatment is suspended could represent a therapeutic option in cells that become resistant by NPM-ALK amplification.

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The next-generation ALK inhibitors

Cited by 29 publications

References 27 publications

The use of cannabinoids as anticancer agents

The use of cannabinoids as anticancer agents

ALK is a therapeutic target for lethal sepsis

Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency

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