Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis

by Selleckchem | Aug 26 2023

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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Merkel cell carcinoma (MCC) is a type of skin cancer that can be difficult to treat and often has limited treatment options. Immune checkpoint inhibitors (ICI) have become the standard of care for advanced MCC, but many patients are ineligible for this treatment, and those who do receive it may develop resistance over time. Therefore, there is an urgent need for alternative therapeutic strategies.

In a recent study, researchers investigated the potential of targeting aurora kinase as a therapeutic approach for MCC. They used patient-derived genetic insights and data generated in their lab to identify aurora kinase as a promising target. Specifically, they examined the efficacy of a highly selective AURKA inhibitor called AK-01 (LY3295668) in six patient-derived MCC cell lines and two MCC cell-line-derived xenograft mouse models.

The results of the study showed that AK-01 effectively suppressed the survival of MCC cells through two mechanisms: apoptosis (programmed cell death) and cell cycle arrest. Notably, AK-01 demonstrated potent activity in MCPyV-negative MCC cells that lacked RB expression. This suggests that AK-01 could be particularly effective in this subset of MCC patients.

Although AK-01 showed promising results in terms of tumor suppression and low toxicity, it had a short in vivo durability upon discontinuation. This means that its effects may not be long-lasting once treatment is stopped. However, the rapid and substantial tumor suppression observed with AK-01 makes it a strong candidate for MCC management, especially when used in combination with existing treatment regimens.

In conclusion, the study findings suggest that AK-01, a highly selective AURKA inhibitor, holds promise as a therapeutic option for MCC, particularly in MCPyV-negative MCC cells without RB expression. Further research and clinical trials will be needed to validate these findings and determine the optimal use of AK-01 in combination with other treatments for MCC patients.