An Aurora kinase inhibitor, <scp>AMG</scp>900, inhibits glioblastoma cell proliferation by disrupting mitotic progression

Ryu, Jaewook; Pyo, Jaehyuk; Lee, Chang-Woo; Kim, Ja Eun

doi:10.1002/cam4.1771

Cited by 12 publications

(7 citation statements)

References 70 publications

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“…Both kinases have been reported as the negative prognostic markers in GB 41 , 42 . Consistently, selective inhibitors of Aurora A [e.g., MLN8237 and VX 689 23 , 30 , 41 , 43 ], Aurora B [e.g., AZD1152-HQPA 21 , 22 ], as well as pan-Aurora inhibitors [e.g., AMG900, ZM 447439 44 , 45 ] have been reported effective in GB cell lines as well as mouse models, when administered either as individual compounds, mixtures with temozolomide, or upon combination with irradiation.…”

Section: Discussionmentioning

confidence: 89%

Viability fingerprint of glioblastoma cell lines: roles of mitotic, proliferative, and epigenetic targets

Lavõgina

Laasfeld

Vardja

et al. 2021

Sci Rep

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Despite the use of multimodal treatment combinations, the prognosis of glioblastoma (GB) is still poor. To prevent rapid tumor recurrence, targeted strategies for the treatment of GB are widely sought. Here, we compared the efficacy of focused modulation of a set of signaling pathways in two GB cell lines, U-251 MG and T98-G, using a panel of thirteen compounds targeting cell cycle progression, proliferation, epigenetic modifications, and DNA repair mechanism. In parallel, we tested combinations of these compounds with temozolomide and lomustine, the standard chemotherapy agents used in GB treatment. Two major trends were found: within individual compounds, the lowest IC50 values were exhibited by the Aurora kinase inhibitors, whereas in the case of mixtures, the addition of DNA methyltransferase 1 inhibitor azacytidine to lomustine proved the most beneficial. The efficacy of cell cycle-targeting compounds was further augmented by combination with radiation therapy using two different treatment regimes. The potency of azacytidine and lomustine mixtures was validated using a unique assay pipeline that utilizes automated imaging and machine learning-based data analysis algorithm for assessment of cell number and DNA damage extent. Based on our results, the combination of azacytidine and lomustine should be tested in GB clinical trials.

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Section: Discussionmentioning

confidence: 89%

Viability fingerprint of glioblastoma cell lines: roles of mitotic, proliferative, and epigenetic targets

Lavõgina

Laasfeld

Vardja

et al. 2021

Sci Rep

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“…Pan-AURKi AMG900 is one of the furthest developed AURKi, showing promising preclinical [ 34 ] and clinical [ 35 ] activity. AMG900 has also been shown to induce senescence in glioblastoma cells [ 36 ]. AZD1152 (barasertib) has been shown to selectively inhibit AURKB and inhibit tumor growth in a dose-dependent manner in different preclinical xenograft models [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity

Punt

Malu

McKenzie

et al. 2020

Cancer Immunol Immunother

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Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance to immunotherapy, patient-derived melanoma cell lines were transduced with 576 open reading frames, or exposed to arrayed libraries of 850 bioactive compounds, prior to co-culture with autologous tumor-infiltrating lymphocytes (TILs). The synergy between the targets and TILs to induce apoptosis, and the mechanisms of inhibiting resistance to TILs were interrogated. Gene expression analyses were performed on tumor samples from patients undergoing immunotherapy for metastatic melanoma. Finally, the effect of inhibiting the top targets on the efficacy of immunotherapy was investigated in multiple preclinical models. Aurora kinase was identified as a mediator of melanoma cell resistance to T-cell-mediated cytotoxicity in both complementary screens. Aurora kinase inhibitors were validated to synergize with T-cell-mediated cytotoxicity in vitro. The Aurora kinase inhibition-mediated sensitivity to T-cell cytotoxicity was shown to be partially driven by p21-mediated induction of cellular senescence. The expression levels of Aurora kinase and related proteins were inversely correlated with immune infiltration, response to immunotherapy and survival in melanoma patients. Aurora kinase inhibition showed variable responses in combination with immunotherapy in vivo, suggesting its activity is modified by other factors in the tumor microenvironment. These data suggest that Aurora kinase inhibition enhances T-cell cytotoxicity in vitro and can potentiate antitumor immunity in vivo in some but not all settings. Further studies are required to determine the mechanism of primary resistance to this therapeutic intervention.

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“…It is a phthalazinamine-based compound which competitively inhibits binding of ATP to the active site of aurora kinases [ 134 ]. Reports have shown that AMG900 inhibited the growth of glioblastoma cells in vitro ultimately leading to cell cycle arrest and senescence [ 135 ]. In MOLM-13 AML cell line, treatment with AMG900 was linked to inhibition of histone H3 phosphorylation, polyploidy and increased apoptosis with the upregulation of p53 [ 136 ].…”

Section: Targeting Aurkb In Cancermentioning

confidence: 99%

Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer

Borah

Reddy

2021

Molecules

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Aurora kinase B (AURKB) is a mitotic serine/threonine protein kinase that belongs to the aurora kinase family along with aurora kinase A (AURKA) and aurora kinase C (AURKC). AURKB is a member of the chromosomal passenger protein complex and plays a role in cell cycle progression. Deregulation of AURKB is observed in several tumors and its overexpression is frequently linked to tumor cell invasion, metastasis and drug resistance. AURKB has emerged as an attractive drug target leading to the development of small molecule inhibitors. This review summarizes recent findings pertaining to the role of AURKB in tumor development, therapy related drug resistance, and its inhibition as a potential therapeutic strategy for cancer. We discuss AURKB inhibitors that are in preclinical and clinical development and combination studies of AURKB inhibition with other therapeutic strategies.

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An Aurora kinase inhibitor, AMG900, inhibits glioblastoma cell proliferation by disrupting mitotic progression

Cited by 12 publications

References 70 publications

Viability fingerprint of glioblastoma cell lines: roles of mitotic, proliferative, and epigenetic targets

Viability fingerprint of glioblastoma cell lines: roles of mitotic, proliferative, and epigenetic targets

Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity

Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer

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