Merkel cell carcinoma (MCC), a neuroendocrine skin cancer, has been increasingly diagnosed since the 1980s, primarily affecting older adults. This cancer is mostly associated with Merkel cell polyomavirus, but some cases may be induced by DNA damage from UV radiation. The challenge of treating recurring MCC, which often shows resistance to existing therapies, underscores the need for innovative treatment methods. The study presented here introduces a new approach to chemo-immunotherapy targeting MCC by combining CDK4/6 inhibitors, which help regulate cell growth, with HIF2α inhibitors, which impact how cancer cells respond to low oxygen levels.
At the University of Washington, Dr. Jung Hyun Lee and her collaborators are leading pioneering efforts to combat Merkel cell carcinoma, a rare yet aggressive form of skin cancer. Their research, published in the esteemed journal Heliyon, has proposed a groundbreaking treatment approach by combining the CDK4/6 inhibitor palbociclib with the HIF2α inhibitor TC-S7009. This novel approach holds the potential to transform the treatment landscape for MCC.
Merkel cell polyomavirus positive MCC often poses a formidable treatment challenges due to cancer recurrence and drug resistance. Dr. Lee’s study aims to target two critical survival mechanisms within cancer cells: regulation of cell division and adaptation to low oxygen conditions. This strategy has been developed to counteract the cancer’s defense mechanisms, especially its ability to evade the immune system.
Palbociclib, renowned for its capacity to disrupt the cell cycle by inhibiting CDK4/6 in cancer cells, demonstrates substantial alterations in cell death when used in combination with TC-S7009. Dr. Lee explains, “Our study has demonstrated that palbociclib induces an increase in ROS, specifically H2O2, leading to heightened expression of HIF-2α, which subsequently upregulates the cancer immune checkpoint inhibitor PD-L1. However, the addition of HIF-2α inhibitor TC-S7009 effectively counteracts these increases and promotes immunogenic cell death in MCC cells, including ferroptosis.”
This drug combination can induce ferroptosis, a form of iron-dependent cell death, by reducing SLC7A11, thereby promoting the destruction of cacner cells. Dr. Lee suggests, “the decrease in SLC7A11, a key regulator of cellular balance crucial to ferroptosis, may be associated with increased levels of lncRNA SLC7A11-AS1, which acts in an anti-sense role to the SLC7A11 gene. Therefore, the combination of CDK4/6 and HIF2α can enhance ferroptosis by simultaneously increasing ROS levels and inhibiting SLC7A11, a central regulator of cellular homeostasis. This strategy holds the potential to significantly increase immunogenic cell death across various MCC cell lines and advance cancer immunotherapy in the future.”
The team proposes a new combination of treaetments guided by examining gene expression patterns, particularly their impact on the immune system, depending on the cell cycle of MCC cells. They have also laid the foundation for significant discoveries by utilizing realistic patient-derived tumor models to test drug combinations and other molecular biology methods.
The implications of this study extend beyond MCC, suggesting new possibilities for cancer therapy. This innovative approach could lead to more effective, targeted treatments for various cancer types. Dr. Lee’s work highlights the importance of understanding and disrupting complex cellular processes in cancer for effective treatment.
This research marks a significant advancement in cancer treatment, particularly in addressing tough cases like MCC. The innovative combination of palbociclib and TC-S7009 might establish a new standard in cancer therapy, offering hope where traditional treatments have been ineffective. This approach could lead to a fundamental shift in how we view and treat various forms of cancer, ultimately improving patient outcomes and quality of life. Further research and clinical trials are vital to fully understand the potential and limitations of this treatment. However, the initial results are promising and lay the groundwork for more comprehensive studies. The collaboration between Dr. Lee and the exceptional research teams at UW exemplifies the continuous endeavor in medicine to develop superior and more effective treatments for life-threatening diseases such as cancer.
JOURNAL REFERENCE
Jung Hyun Lee et al. “Enhancing immunogenic responses through CDK4/6 and HIF2α inhibition in Merkel cell carcinoma,” Heliyon, 2024. DOI: https://doi.org/10.1016/j.heliyon.2023.e23521.
