Inhibition of Aurora A Kinase in Combination with Chemotherapy Induces Synthetic Lethality and Overcomes Chemoresistance in Myc-Overexpressing Lymphoma

Park, Steven I; Lin, Carolina P.; Ren, Natalie; Dittmer, Dirk P.; Foote, Michael B.; Parton, Trevor; Bhatt, Aadra P.; Fedoriw, Yuri; Röth, Daniel; Cann, Marissa L.; Johnson, Gary L.; Damania, Blossom

doi:10.1007/s11523-019-00662-4

Cited by 13 publications

(8 citation statements)

References 49 publications

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“…Interestingly, 1 recent study has found that inhibition of AURKA in combination with chemotherapy induces synthetic lethality and overcomes chemoresistance in MYC-overexpressing lymphoma, including non-Hodgkin lymphoma. 40 Dauch et al recently demonstrated a direct binding of AURKA to MYC, which results in the stabilization of MYC protein. 41 Interestingly, our recent data showed that treatment with either analog 315 or 403 significantly reduced MYC expression from PEL cells (supplemental Figure 8).…”

Section: Discussionmentioning

confidence: 99%

Developing new ceramide analogs and identifying novel sphingolipid-controlled genes against a virus-associated lymphoma

Chen

Goyal

Dai

et al. 2020

Blood

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Primary effusion lymphoma (PEL) is an aggressive malignancy with poor prognosis even under chemotherapy, usually infected by Kaposi's sarcoma-associated herpesvirus (KSHV), one of human oncogenic viruses. Currently, there is no specific treatment for PEL, therefore developing new therapies is of high importance. Sphingolipid metabolism plays an important role in determining the fate of tumor cells. Our previous studies have demonstrated that there is a correlation between sphingolipid metabolism and KSHV+ tumor cells survival. To further develop sphingolipid metabolism targeted therapy, after screening a series of newly synthesized ceramide analogs, here, we have identified compounds with effective anti-PEL activity. These compounds induce significant PEL apoptosis, cell cycle arrest, and intracellular ceramide production through regulation of ceramide synthesizing or ceramide metabolizing enzymes, and dramatically suppress tumor progression without visible toxicity in vivo. These new compounds also increase viral lytic gene expression in PEL cells. Our comparative transcriptomic analysis revealed their mechanisms of action for inducing PEL cell death, and identified a subset of novel cellular genes including AURKA and CDCA3, controlled by sphingolipid metabolism, and required for PEL survival with functional validation. These data provide the framework for the development of promising sphingolipid-based therapies against this virus-associated malignancy.

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Section: Discussionmentioning

confidence: 99%

Developing new ceramide analogs and identifying novel sphingolipid-controlled genes against a virus-associated lymphoma

Chen

Goyal

Dai

et al. 2020

Blood

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“…plus rituximab and vincristine is well tolerated and demonstrates activity against non-germinal center B-cell DLBC [191]. In a study on Myc-overexpressing lymphoma xenografts, a combination of cyclophosphamide and MLN8237 induced complete tumor regression in all mice, leading to improvements in survival [192].…”

Section: Combination Therapymentioning

confidence: 99%

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

et al. 2021

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Aurora kinase A (AURKA) belongs to the family of serine/threonine kinases, whose activation is necessary for cell division processes via regulation of mitosis. AURKA shows significantly higher expression in cancer tissues than in normal control tissues for multiple tumor types according to the TCGA database. Activation of AURKA has been demonstrated to play an important role in a wide range of cancers, and numerous AURKA substrates have been identified. AURKA-mediated phosphorylation can regulate the functions of AURKA substrates, some of which are mitosis regulators, tumor suppressors or oncogenes. In addition, enrichment of AURKA-interacting proteins with KEGG pathway and GO analysis have demonstrated that these proteins are involved in classic oncogenic pathways. All of this evidence favors the idea of AURKA as a target for cancer therapy, and some small molecules targeting AURKA have been discovered. These AURKA inhibitors (AKIs) have been tested in preclinical studies, and some of them have been subjected to clinical trials as monotherapies or in combination with classic chemotherapy or other targeted therapies.

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“…Aurora kinases (AURK) are mitotic regulators often overexpressed in cancer, including pediatric ALL (137). The AURKA inhibitor alisertib (MLN8237) had shown promising results for both ALL and lymphoma cells in vitro (138). Unfortunately, a phase II clinical trial from the Children's Oncology Group reported objective response after alisertib single-agent treatment in less than 5% of the pediatric patients with recurrent/ refractory advanced solid tumor or acute leukemia (139).…”

Section: Other Promising Targeted Treatments In Developmentmentioning

confidence: 99%

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

Cordó

Zwet

Canté-Barrett

et al. 2021

Blood Cancer Discovery

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy characterized by aberrant proliferation of immature thymocytes. Despite an overall survival of 80% in the pediatric setting, 20% of patients with TALL ultimately die from relapsed or refractory disease. Therefore, there is an urgent need for novel therapies. Molecular genetic analyses and sequencing studies have led to the identification of recurrent TALL genetic drivers. This review summarizes the main genetic drivers and targetable lesions of TALL and gives a comprehensive overview of the novel treatments for patients with TALL that are currently under clinical investigation or that are emerging from preclinical research. Significance: TALL is driven by oncogenic transcription factors that act along with secondary acquired mutations. These lesions, together with active signaling pathways, may be targeted by therapeutic agents. Bridging research and clinical practice can accelerate the testing of novel treatments in clinical trials, offering an opportunity for patients with poor outcome.

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Inhibition of Aurora A Kinase in Combination with Chemotherapy Induces Synthetic Lethality and Overcomes Chemoresistance in Myc-Overexpressing Lymphoma

Cited by 13 publications

References 49 publications

Developing new ceramide analogs and identifying novel sphingolipid-controlled genes against a virus-associated lymphoma

Developing new ceramide analogs and identifying novel sphingolipid-controlled genes against a virus-associated lymphoma

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

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