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

Abstract

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.

Apoptosis is responsible for the cytotoxic effects of anti-GD2 ganglioside antibodies and aurora A kinase inhibitors on human neuroblastoma cells

“…Additionally, the results indicated that inhibitors of RIP kinases may potentiate apoptosis induced by aurora A kinase inhibitors. Most aurora A kinase inhibitors have been reported to induce apoptosis and the results of the current study are complimented by these reports (Boss et al, 2009;Nair et al, 2012;Shang et al, 2017;Das et al, 2021). However, Martens and others (2018) demonstrated that the pan-aurora kinase inhibitor, Tozasertib (VX-680; MK-0457), is a potent inhibitor of necroptosis.…”

Combination of an aurora kinase inhibitor and the ABL tyrosine kinase inhibitor asciminib against ABL inhibitor-resistant CML cells

“…LY3295668, a selective inhibitor of AURKA, has demonstrated a high level of selectivity, with over 1000-fold greater potency against AURKA than AURKB. In addition, LY3295668 has shown anti-tumor activity in various cancer cell lines and animal models [ 22 ]. Encouragingly, LY3295668 has also exhibited anti-tumor activity in patients with advanced or metastatic solid tumors, with a tolerable toxicity profile in phase I clinical trials [ 22 ].…”

“…In addition, LY3295668 has shown anti-tumor activity in various cancer cell lines and animal models [ 22 ]. Encouragingly, LY3295668 has also exhibited anti-tumor activity in patients with advanced or metastatic solid tumors, with a tolerable toxicity profile in phase I clinical trials [ 22 ]. In the phase I study, plasma concentrations of LY3295668 from 13 patients were analyzed [ 23 ].…”

Merkel Cell Carcinoma Display PIEZO2 Immunoreactivity

“…In any case, although in the presented MCC cases there is no evidence of a prognostic value of PIEZO2, MCC could benefit from a possible PIEZO related therapy, as long as both types of PIEZO channels are known to be inhibited by the toxin GsMTx4 and stimulated by Yoda1 [ 34 ]. Other promising therapies are in study or already in use, such as PD-1/PDL-1 pathway blocking agents, multi-targeted tyrosine kinase inhibitors, MCPyV-related immunotherapy and AURKA inhibitors, potentially useful in MCPyV-negative MCC, among others [ 9 , 10 , 35 , 36 ].…”