Researchers have made significant strides toward improving treatments for Merkel cell carcinoma (MCC), a rare and aggressive form of skin cancer. A recent study utilized high-throughput screening techniques to identify Aurora kinase B (AURKB) as a promising therapeutic target. The findings suggest enhanced efficacy of the AURKB inhibitor AZD2811, which shows potential for treating both virus-positive and virus-negative subtypes of MCC.
MCC poses considerable treatment challenges, with standard chemotherapy often falling short for many patients. Traditionally, immune checkpoint inhibitors like PD-(L)1 have been employed, but they fail to provide durable responses for nearly half of the patients. This drives the urgent need for innovative therapies capable of addressing the distinct patient needs.
The study involved screening around 4,000 compounds, including numerous FDA-approved drugs, to assess their ability to reduce the viability of MCC cells. Notably, the researchers employed RNA interference to pinpoint AURKB as not only important for cancer cell survival but also selectively dependent on by various MCC subtypes.
AURKB, along with its counterparts AURKA and AURKC, belongs to the serine/threonine kinase family responsible for cell-cycle regulation, which is often disrupted in cancer. Among the screened compounds, AURKB inhibitors proved particularly effective against virus-positive MCC (VP-MCC). This type of cancer accounts for around 80% of all MCC cases and is characterized by the integration of Merkel cell polyomavirus (MCPyV) DNA.
AZD2811, the selective AURKB inhibitor, was found to not only induce mitotic dysregulation but also prompt apoptosis—the programmed cell death—especially within VP-MCC cells. When tested on xenograft models of both VP-MCC and virus-negative MCC (VN-MCC), AZD2811 nanoparticles demonstrated significant tumor shrinkage and extended survival rates.
Importantly, the study underscored the differing response profiles between VP-MCC and VN-MCC cells, leading to distinct therapeutic strategies for each subtype. The authors noted, “Overall, our unbiased screens identify AURKB as a promising therapeutic target and AZD2811NP as a potential treatment for MCC,” highlighting the broader impact of this discovery.
AZD2811's mechanism of action includes the inhibition of AURKB-mediated phosphorylation of Histone 3, which is pivotal for proper chromosome condensation during cell division. This blockage disrupts mitosis, leading to catastrophic failures within the cancer cells, driving them toward death. The effective targeting of AURKB could usher in new personalized treatment plans, especially as the study also revealed similar levels of AURKB expression across various cell types, reinforcing its potential universal target status.
The article mentions, “This is the first time we are seeing such clear evidence of selective AURKB dependence for these cancer types, allowing for targeted approaches.” By identifying both viral and mutation profiles within MCC subtypes, the findings could change how current treatment pathways are developed, particularly for those who are resistant to established therapies.
Through combining advanced drug screening methodologies with comprehensive genetic analysis, the research paves the way for targeted, innovative therapies to combat MCC. This focus on AURKB may represent just the beginning of redefining cancer treatment for patients with advanced MCC, potentially offering hope where none previously existed.
Such targeted treatments may eventually lead to improved patient outcomes, lower recurrence rates, and overcome the barriers often faced by MCC patients. The continued exploration of AURKB and other novel avenues opens exciting opportunities for future cancer therapies, promising to reshape the approach to one of the most aggressive skin cancers recognized to date.