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|Ref Type||Journal Article|
|Authors||Das BK, Kannan A, Nguyen Q, Gogoi J, Zhao H, Gao L|
|Title||Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis.|
|Date||2021 Jul 23|
|Abstract Text||Merkel cell carcinoma (MCC) is an often-lethal skin cancer with increasing incidence and limited treatment options. Although immune checkpoint inhibitors (ICI) have become the standard of care in advanced MCC, 50% of all MCC patients are ineligible for ICIs, and amongst those treated, many patients develop resistance. There is no therapeutic alternative for these patients, highlighting the urgent clinical need for alternative therapeutic strategies. Using patient-derived genetic insights and data generated in our lab, we identified aurora kinase as a promising therapeutic target for MCC. In this study, we examined the efficacy of the recently developed and highly selective AURKA inhibitor, AK-01 (LY3295668), in six patient-derived MCC cell lines and two MCC cell-line-derived xenograft mouse models. We found that AK-01 potently suppresses MCC survival through apoptosis and cell cycle arrest, particularly in MCPyV-negative MCC cells without RB expression. Despite the challenge posed by its short in vivo durability upon discontinuation, the swift and substantial tumor suppression with low toxicity makes AK-01 a strong potential candidate for MCC management, particularly in combination with existing regimens.|
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|RB1 loss||Merkel cell carcinoma||sensitive||LY3295668||Preclinical - Pdx & cell culture||Actionable||In a preclinical study, LY3295668 resulted in cell growth inhibition and increased cell cycle arrest and apoptosis in Merkel cell carcinoma patient-derived cell lines with loss of Rb1 expression in culture, and resulted in reduced tumor growth in a patient-derived xenograft (PDX) model (PMID: 34359608).||34359608|