Crizotinib, a MET inhibitor, inhibits growth, migration, and invasion of breast cancer cells in vitro and synergizes with chemotherapeutic agents

Ayoub, Nehad M.; Al-Shami, Kamal M.; Alqudah, Mohammad; Mhaidat, Nizar M.

doi:10.2147/ott.s148604

Cited by 27 publications

(27 citation statements)

References 67 publications

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“…Therefore, we investigated whether sacral and clival chordoma cells respond differently to a treatment with cMET inhibitors. The dual MET/ALK inhibitor crizotinib showed a dose-dependent reduction of viability in various breast cancer cell lines after 48 h of treatment, with an IC 50 of 5–10 µM 18 , which is similar to the IC 50 obtained in our HGF-stimulated, crizotinib-treated chordoma cells. Yakes et al tested the effect of cabozantinib, a small molecule tyrosine kinase inhibitor, on the proliferation behavior of different tumor cell lines and achieved different effects with respect to cMET amplification and IC 50 concentrations 19 .…”

Section: Discussionsupporting

confidence: 80%

Higher cMET dependence of sacral compared to clival chordoma cells: contributing to a better understanding of cMET in chordoma

Lohberger

Scheipl

Heitzer

et al. 2021

Sci Rep

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Chordomas are rare slow growing, malignant bone tumors of the axial skeleton with no approved medical treatment. As the majority of chordomas express cMET and its ligand, HGF, and crosstalks between EGFR and MET-signaling exist, we aimed to explore cMET activity in chordoma cell lines and clinical samples. We investigated nine chordoma patients and four chordoma cell lines for cMET expression. Two clival and two sacral chordoma cell lines were tested for chromosomal abnormalities of the MET gene locus; we studied the influence of HGF on the autocrine secretion and migration behavior, as well as protein expression and phosphorylation. Two MET/ALK inhibitors were investigated for their effects on cell viability, cell cycle, cyclin alterations, apoptosis, and downstream signaling pathways. Moderate and strong expression of membrane and cytoplasmic cMET in chordoma patients and cell lines used, as well as concentration-dependent increase in phospho cMET expression after HGF stimulation in all four chordoma cell lines was shown. U-CH2, MUG-Chor1, and UM-Chor1 are polysomic for MET. Chordoma cell lines secreted EGF, VEGF, IL-6, and MMP9 upon HGF-stimulation. Sacral cell lines showed a distinct HGF-induced migration. Both inhibitors dose-dependently inhibited cell growth, induce apoptosis and cell-cycle arrest, and suppress downstream pathways. Heterogeneous responses obtained in our in vitro setting indicate that cMET inhibitors alone or in combination with other drugs might particularly benefit patients with sacral chordomas.

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Section: Discussionsupporting

confidence: 80%

Higher cMET dependence of sacral compared to clival chordoma cells: contributing to a better understanding of cMET in chordoma

Lohberger

Scheipl

Heitzer

et al. 2021

Sci Rep

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“…Our observations of dose‐dependent inhibition of HGF/R c‐MET phosphorylation by ICY‐5 in BC cells is therefore in line with previous literature, and resulted in the control of BC cell proliferation through the MET‐HGF axis. c‐MET activation plays a central role in BC progression (Ayoub, Al‐Shami, Alqudah, & Mhaidat, 2017). Previous studies showed that activated c‐MET promotes BC cell scattering, migration, and invasion following HGF ligand activation (Lawrence & Salgia, 2010).…”

Section: Discussionmentioning

confidence: 99%

Computational and in vitro characterization of ICY‐5: A potential candidate promoting mitochondrial apoptosis via the c‐MET and STAT3 pathways

Shahrani

Balasubramaniam

Alshahrani

et al. 2020

Journal Cellular Physiology

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Targeted chemotherapy remains the primary choice in controlling various forms of breast cancer (BC) due to its heterogenous gene expressions in various subtypes. In silico and in vitro evaluation of ICY-5, a novel arylidene analogue against c-MET, was performed. ICY-5 exhibited a docking score of −9.6 kcal/mol in inactive conformation and, − 8.6 kcal/mol in active conformation for c-MET. ICY-5 inhibited c-MET enzyme with an IC 50 of 34.34 nM. The compound effectively inhibited MDA-MB 231 and MCF-7 cell proliferation, with GI 50 values of 62.61 and 75.31 nM, respectively, and hepatocyte growth factor (HGF)/R c-MET phosphorylation with IC 50 s of 71.41 and 83.77 nM, respectively. ICY-5 dose-dependently inhibited HGF-induced transmigration, cell scattering, invasion and altered cell cycle. An increase in apoptotic populations of these cells, with a dose-dependent decease in phosphorylation of STAT3 protein was observed. Furthermore, ICY-5 upregulated the caspase-3, caspase-9, Bcl-2-associated X and survivin, and downregulated Bcl-2, vascular endothelial growth factor, matrix metalloproteinase-2 (MMP-2), and MMP-9 in both BC cell lines. In summary, ICY-5 exhibited excellent efficacy in BC cells, targeting c-MET/SAT-3-mediated mitochondrial apoptosis. Further research will be required to ascertain ICY-5 suitability as a targeted chemotherapeutic against multiple forms of BC.

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“…Crizotinib (or PF-02341066) is an ATP-competitive small-molecule inhibitor which blocks MET, anaplastic lymphoma receptor tyrosine kinase (ALK), c-ros oncogene 1 receptor tyrosine kinase (ROS1) and AXL. In breast cancer cell lines, it inhibits cellular proliferation [ 128 , 129 ]. As described for the other non-selective inhibitors, crizotinib is also involved in several clinical trials as a modulator of other molecular targets [ 22 ].…”

Section: Axl Inhibition In Breast Cancer Treatmentmentioning

confidence: 99%

AXL Receptor in Breast Cancer: Molecular Involvement and Therapeutic Limitations

Falcone

Bazzichetto

Bria

et al. 2020

IJMS

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Breast cancer was one of the first malignancies to benefit from targeted therapy, i.e., treatments directed against specific markers. Inhibitors against HER2 are a significant example and they improved the life expectancy of a large cohort of patients. Research on new biomarkers, therefore, is always current and important. AXL, a member of the TYRO-3, AXL and MER (TAM) subfamily, is, today, considered a predictive and prognostic biomarker in many tumor contexts, primarily breast cancer. Its oncogenic implications make it an ideal target for the development of new pharmacological agents; moreover, its recent role as immune-modulator makes AXL particularly attractive to researchers involved in the study of interactions between cancer and the tumor microenvironment (TME). All these peculiarities characterize AXL as compared to other members of the TAM family. In this review, we will illustrate the biological role played by AXL in breast tumor cells, highlighting its molecular and biological features, its involvement in tumor progression and its implication as a target in ongoing clinical trials.

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Crizotinib, a MET inhibitor, inhibits growth, migration, and invasion of breast cancer cells in vitro and synergizes with chemotherapeutic agents

Cited by 27 publications

References 67 publications

Higher cMET dependence of sacral compared to clival chordoma cells: contributing to a better understanding of cMET in chordoma

Higher cMET dependence of sacral compared to clival chordoma cells: contributing to a better understanding of cMET in chordoma

Computational and in vitro characterization of ICY‐5: A potential candidate promoting mitochondrial apoptosis via the c‐MET and STAT3 pathways

AXL Receptor in Breast Cancer: Molecular Involvement and Therapeutic Limitations

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