Critical risk-benefit assessment of the novel anti-cancer aurora a kinase inhibitor alisertib (MLN8237): A comprehensive review of the clinical data

Tayyar, Yaman; Jubair, Luqman; Fallaha, Sora; McMillan, Nigel A.J.

doi:10.1016/j.critrevonc.2017.09.006

Cited by 39 publications

(38 citation statements)

References 55 publications

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“…The clinical efficacy of alisertib vary depending on the tumor type, and some cases of serious side effects have been described 65 . However, the potential clinical effect of alisertib is promising as it improved progression-free survival and the duration of disease stability for various tumor types, and the reported side effects were manageable in many cases 66 . To date, clinical studies of AURKA inhibitors in hematologic malignancies have moved fast, but there has been slow progress in solid tumor studies.…”

Section: Discussionmentioning

confidence: 99%

Targeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells

et al. 2018

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ARID1A, a component of the SWI/SNF chromatin remodeling complex, is a tumor suppressor with a high frequency of inactivating mutations in many cancers. Therefore, ARID1A deficiency has been exploited therapeutically for treating cancer. Here we show that ARID1A has a synthetic lethal interaction with aurora kinase A (AURKA) in colorectal cancer (CRC) cells. Pharmacological and genetic perturbations of AURKA selectively inhibit the growth of ARID1A-deficient CRC cells. Mechanistically, ARID1A occupies the AURKA gene promoter and negatively regulates its transcription. Cells lacking ARID1A show enhanced AURKA transcription, which leads to the persistent activation of CDC25C, a key protein for G2/M transition and mitotic entry. Inhibiting AURKA activity in ARID1A-deficient cells significantly increases G2/M arrest and induces cellular multinucleation and apoptosis. This study shows a novel synthetic lethality interaction between ARID1A and AURKA and indicates that pharmacologically inhibiting the AURKA–CDC25C axis represents a novel strategy for treating CRC with ARID1A loss-of-function mutations.

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Section: Discussionmentioning

confidence: 99%

Targeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells

et al. 2018

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“…These studies support the role of Aurora inhibitors as potential MYC-destabilizing therapeutics and suggest that MYC expression may be used as a biomarker for patient response. However, despite promising data, clinical trials with MLN8237 have raised concerns about the safety profile of this compound, with a number of trials resulting in significant toxicities and disease progression [189].…”

Section: Targeting Myc Stabilitymentioning

confidence: 99%

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Allen-Petersen¹,

Sears²

2019

BioDrugs

134

110

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MYC is a master transcriptional regulator that controls almost all cellular processes. Over the last several decades, researchers have strived to define the context-dependent transcriptional gene programs that are controlled by MYC, as well as the mechanisms that regulate MYC function, in an effort to better understand the contribution of this oncoprotein to cancer progression. There are a wealth of data indicating that deregulation of MYC activity occurs in a large number of cancers and significantly contributes to disease progression, metastatic potential, and therapeutic resistance. Although the therapeutic targeting of MYC in cancer is highly desirable, there remain substantial structural and functional challenges that have impeded direct MYC-targeted drug development and efficacy. While efforts to drug the 'undruggable' may seem futile given these challenges and considering the broad reach of MYC, significant strides have been made to identify points of regulation that can be exploited for therapeutic purposes. These include targeting the deregulation of MYC transcription in cancer through small-molecule inhibitors that induce epigenetic silencing or that regulate the G-quadruplex structures within the MYC promoter. Alternatively, compounds that disrupt the DNA-binding activities of MYC have been the long-standing focus of many research groups, since this method would prevent downstream MYC oncogenic activities regardless of upstream alterations. Finally, proteins involved in the post-translational regulation of MYC have been identified as important surrogate targets to reduce MYC activity downstream of aberrant cell stimulatory signals. Given the complex regulation of the MYC signaling pathway, a combination of these approaches may provide the most durable response, but this has yet to be shown. Here, we provide a comprehensive overview of the different therapeutic strategies being employed to target oncogenic MYC function, with a focus on post-translational mechanisms.

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“…Together with cell biological evidence that inhibition of AurA compromises mitotic progression, an increased AurA expression profile in cancer supports that AurA is a clinically relevant drug target (48). Pharmaceutical companies have begun to exploit this possibility, bringing numerous targeted inhibitors to the market as anti-cancer drugs, and spurring clinical trials (37,(49)(50)(51)(52)(53)(54)(55). However, while the efficacy and safety of inhibiting AurA have been supported by preclinical and early stage clinical trials, response to AurA inhibition has been limited (37, 55-57) and it remains unclear which patients may best benefit from AurA inhibitor treatment either alone, or in combination with standard chemotherapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

“…AML is a cancer context where AurA kinase is often amplified, and where its inhibition is actively being exploited in preclinical and clinical approaches (35)(36)(37). Western blot and qPCR analyses demonstrate that AurA expression in these cell lines, independent of cell cycle distribution, range from levels comparable to that of the non-transformed RPE-1 cell line (ie HL60), to levels over 8-fold higher than that seen in RPE-1 cells (ie K562) ( Figure 4A Figure 4E & F).…”

Section: Centrosome Number Corresponds With Response To Aurora a Inhimentioning

confidence: 99%

Aurora A inhibition limits centrosome clustering and promotes mitotic catastrophe in cells with supernumerary centrosomes

Navarro-Serer¹,

Childers²,

Hermance³

et al. 2018

Preprint

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The presence of supernumerary centrosomes is prevalent in cancer, where they promote the formation of transient multipolar mitotic spindles. Active clustering of supernumerary centrosomes enables the formation of a functional bipolar spindle that is competent to complete a bipolar division. Disruption of spindle pole clustering in cancer cells promotes multipolar division and generation of non-proliferative daughter cells with compromised viability. Hence molecular pathways required for spindle pole clustering in cells with supernumerary centrosomes, but dispensable in normal cells, are promising therapeutic targets. Here we demonstrate that Aurora A kinase activity is required for spindle pole clustering in cells with extra centrosomes. While cells with two centrosomes are ultimately able to build a bipolar spindle and proceed through a normal cell division in the presence of Aurora A inhibition, cells with supernumerary centrosomes form multipolar and disorganized spindles that are not competent for chromosome segregation. Instead, following a prolonged mitosis, these cells experience catastrophic divisions that result in grossly aneuploid, and non-proliferative daughter cells. Aurora A inhibition in a panel of Acute Myeloid Leukemia cancer cells has a similarly disparate impact on cells with supernumerary centrosomes, suggesting that centrosome number and spindle polarity may serve as predictive biomarkers for response to therapeutic approaches that target Aurora A kinase function.

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Critical risk-benefit assessment of the novel anti-cancer aurora a kinase inhibitor alisertib (MLN8237): A comprehensive review of the clinical data

Cited by 39 publications

References 55 publications

Targeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells

Targeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Aurora A inhibition limits centrosome clustering and promotes mitotic catastrophe in cells with supernumerary centrosomes

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