Since the 1980s, Merkel cell carcinoma (MCC) has been increasingly diagnosed with neuroendocrine skin cancer (a type of neuroendocrine carcinoma), which mainly affects the elderly. The cancer is mainly associated with Merkel cell polyomavirus, but some cases may be due to DNA damage caused by ultraviolet radiation. The challenge of treatment of recurrent MCCs that often demonstrate resistance to existing therapies highlights the need for innovative treatments. The study presented here introduces a new approach to targeting MCC by combining CDK4/6 inhibitors to new methods that help regulate cell growth, which can affect cancer cells. Reactions of low oxygen levels.
At the University of Washington, Dr. Jung Hyun Lee and her collaborators are leading groundbreaking efforts with Merkel’s cell carcinoma, a rare but aggressive form of skin cancer. Their study, published in the journal Dear Heliyon, proposes a groundbreaking treatment by combining the CDK4/6 inhibitor palbociclib with the HIF2α inhibitor TC-S7009. This novel approach has the potential to change the therapeutic landscape of MCC.
Merkel cell polyomavirus-positive MCCs often present huge therapeutic challenges due to cancer recurrence and drug resistance. Dr. Lee’s research aims to target two key survival mechanisms within cancer cells: regulating cell division and adapting to hypoxic conditions. This strategy has been developed to counteract cancer defense mechanisms, especially the ability to evade the immune system.
Palbociclib is known for its ability to disrupt the cell cycle by inhibiting CDK4/6 in cancer cells, and when used in combination with TC-S7009, cell death undergoes significant changes. Dr Lee explained: “Our study shows that Palbociclib induces an increase in ROS, especially H2o2resulting in enhanced HIF-2α expression, which subsequently upregulated the cancer immune checkpoint inhibitor PD-L1. However, addition of the HIF-2α inhibitor TC-S7009 effectively counteracted these increases and promoted immunogenic cell death in MCC cells, including iron toxic cells. ”
This drug combination can promote the destruction of Cacner cells by reducing SLC7A11, thereby inducing a form of iron-dependent cell death. Dr Lee suggested: “Reduction of SLC7A11 is a key regulator of cellular balance that is critical to bolt toxicity and may be associated with an elevated level of LNCRNA SLC7A11-AS1, which has antisense effects with the SLC7A11 gene. Therefore, CDK4/6 and The combination of HIF2α can enhance iron phagocytosis by simultaneously increasing ROS levels and inhibiting cellular homeostasis. This strategy has the potential to significantly increase immunogenic death in various MCC cell lines and improve cancer immunotherapy in the future .”
The team proposed a new combination of disconnections directed by examining gene expression patterns, especially their effects on the immune system, depending on the cell cycle of MCC cells. They also laid the foundation for major discoveries by leveraging realistic patient-derived tumor models to test drug combinations and other molecular biology methods.
The implications of this study go beyond MCC, suggesting new possibilities for cancer treatment. This innovative approach may lead to more effective, targeted treatments targeting a variety of cancer types. Dr. Lee’s work emphasizes the importance of understanding and disrupting complex cellular processes in cancer for effective treatment.
This study marks a significant advance in cancer treatment, especially in addressing difficult cases such as MCC. The innovative combination of Palbociclib and TC-S7009 may establish new standards for cancer treatment, providing hope where traditional therapies are ineffective. This approach may lead to how we view and treat various forms of cancer, ultimately improving patients’ outcomes and quality of life. Further research and clinical trials are essential to fully understand the potential and limitations of this treatment. However, the initial results are promising and lay the foundation for a more comprehensive study. The collaboration between Dr. Lee and UW’s outstanding research team illustrates the ongoing efforts in the field of medicine to develop superior and more effective treatments for higher life-threatening diseases such as cancer.
Journal Reference
Jung Hyun Lee et al. “Enhance the immunogenic response through HIF2α inhibition in CDK4/6 and Merkel cell carcinoma,” Heliyon, 2024. DOI: DOI:
