AMG 900, a Small-Molecule Inhibitor of Aurora Kinases, Potentiates the Activity of Microtubule-Targeting Agents in Human Metastatic Breast Cancer Models

Preface Cancer is characterized by uncontrolled proliferation resulting from aberrant activity of various cell cycle proteins; therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrated that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. In contrast, many cancers are uniquely dependent on these proteins and are hence selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle. Here, we review the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as future therapeutic potential of various inhibitors. We focus only on proteins that directly regulate cell cycle progression. Cyclin-dependent kinases with transcriptional functions, as well as PARP inhibitors, which are highly successful in targeting BRCA1/BRCA2-mutant tumours, are not covered by this review.

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“…Caused tumour regression in combination with ixabepilone in triple-negative breast cancer xenografts 304 …”

Section: Figurementioning

confidence: 99%

Cell cycle proteins as promising targets in cancer therapy

2017

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“…Breast cancer ranks as the second cause of cancer death among women (1)(2)(3)(4). Clinical cases have indicated that most of the breast cancer deaths are caused by metastasis (5,6), and as a distinct metastatic pattern, breast cancer cells are more inclined to migrate into lymph nodes, bone marrow, lung, liver and brain (7).…”

Section: Introductionmentioning

confidence: 99%

PEG10 promotes human breast cancer cell proliferation, migration and invasion

Xiao

Tembo

et al. 2016

International Journal of Oncology

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Abstract. Paternally expressed imprinted gene 10 (PEG10), derived from the Ty3/Gypsy family of retrotransposons, has been implicated as a genetic imprinted gene. Accumulating evidence suggests that PEG10 plays an important role in tumor growth in various cancers, including hepatocellular carcinoma, lung cancer and prostate cancer. However, the correlation between PEG10 and breast cancer remains unclear.In the present study, we evaluated and characterized the role of PEG10 in human breast cancer proliferation, cell cycle, clone formation, migration and invasion. The expression level of PEG10 was significantly elevated in breast cancer tissues and associated with distant metastasis and poor clinical outcome. Gene set enrichment analysis indicated that high expression of PEG10 could enrich cell cycle-related processes in breast cancer tissues. Ectopic overexpression of PEG10 in breast cancer cells enhanced cell proliferation, cell cycle, clone formation along with migration and invasion. Cell-to-cell junction molecule E-cadherin was downregulated and matrix degradation proteases MMP-1, MMP-2, MMP-9 were up regulated after PEG10 overexpression. Our results demonstrated that PEG10 is a crucial oncogene and has prognostic value for breast cancer, which could be applied in breast cancer diagnosis and targeting therapy in future.

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“…In the case of NIMA, knockdown of this gene in triple negative tumors induced cell cycle arrest followed by cell death [34]. Similarly, targeting aurora kinases A and B has shown an antitumoral effect in TNBC and these agents were synergistic with MEK inhibitors and agents targeting microtubules [35, 36]. …”

Section: Novel Therapeutic Possibilities In Tnbcmentioning

confidence: 99%

Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies

Ocaña

Pandiella

2017

Oncotarget

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Triple negative breast cancer (TNBC) is still an incurable disease despite the great scientific effort performed during the last years. The huge heterogeneity of this disease has motivated the evaluation of a great number of therapies against different molecular alterations. In this article, we review the biological bases of this entity and how the known molecular evidence supports the current preclinical and clinical development of new therapies. Special attention will be given to ongoing clinical studies and potential options for future drug combinations.

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AMG 900, a Small-Molecule Inhibitor of Aurora Kinases, Potentiates the Activity of Microtubule-Targeting Agents in Human Metastatic Breast Cancer Models

Cited by 47 publications

References 39 publications

Cell cycle proteins as promising targets in cancer therapy

Cell cycle proteins as promising targets in cancer therapy

PEG10 promotes human breast cancer cell proliferation, migration and invasion

Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies

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