Cancer is a famously complex disease. Despite sharing the ‘cancer’ label, different cancer types can be as structurally and functionally diverse as the tissues from which they arise—physicians and scientists often dedicate their entire lives to understanding the idiosyncrasies of just a tiny subset of human cancers. It is unreasonable, then, to expect the treatment for such a complex disease to be simple. Accordingly, most cancer patients today are treated not with a single medicine but with so-called ‘combination therapy’ consisting of traditional treatments (surgery, radiation and chemotherapy) as well as a new era of precision therapeutics tailored to the specific molecular characteristics of their tumor. A significant yet less flashy aspect of current cancer research efforts today is dedicated not to developing new precision therapies but to figuring out the best way to combine existing therapies to treat particular types of cancers.
Our story today comes from Drs. Jung Hyun Lee and Paul Nghiem, researchers affiliated with the Fred Hutch Clinical Research Division and the University of Washington School of Medicine, who primarily study Merkel Cell Carcinoma (MCC), an aggressive skin cancer commonly caused by the oncogenic Merkel cell polyomavirus. MCC often responds to a type of cancer immunotherapy targeting a receptor pair known as PD-1/PD-L1 (conveniently discussed in my other spotlight this month), but often recurs following treatment, underscoring the need for a different treatment strategy. The team’s recent publication in Heliyon investigates such a strategy, using a combination of two drugs—one which targets the cell cycle, and the other which targets a compensatory stress response triggered by cell cycle inhibition.
The important biomarker PD-L1, expressed in tumor cells, plays an immunosuppressive role, allowing tumors to evade immune surveillance (see here for more details). Interestingly, PD-L1 expression is very low in major MCC cell lines, particularly in those driven by the aforementioned Merkel Cell polyomavirus. After confirming this phenomenon in an RNA-sequencing dataset from a patient with MCC, Lee and colleagues examined virus-positive MCC cell lines to discern whether MCC cells consistently display low PD-L1 expression. Surprisingly, they found that PD-L1 expression fluctuated considerably during the cell cycle: cells in G2/M phases (right before cell division) accumulated PD-L1, while cells in G1 phase (right after cell division) showed lower PD-L1 expression. This clue, in combination with a few others from the aforementioned sequencing dataset, led Lee and team to test an FDA-approved drug called Palbociclib—an inhibitor of a pair of cyclin-dependent kinases, CDK4/6 (active during G1 phase)—on MCC cells and tumor xenograft models. In both models, Palbociclib dose-dependently increased PD-L1 levels and enhanced cell death.
Ideally, Palbociclib would eliminate MCC cells without increasing PD-L1 and potentially suppressing immune responses. Therefore, Lee and colleagues shifted their focus to understanding how Palbociclib induced PD-L1 expression. They assessed the levels of several transcription factors involved in PD-L1 regulation, among which only one—hypoxia-inducible factor 2α (HIF-2α)—showed a neatly dose-dependent increase in response to Palbociclib treatment. This turned out to be more than a lucky coincidence, as the team had access to a new small molecule called TC-S7009, which is a potent and selective HIF-2α inhibitor. Gratifyingly, MCC cells treated with both Palbociclib and this HIF-2α inhibitor showed no increase in PD-L1. In addition to suppressing the induction of PD-L1, the team noted another interesting observation: the combination of Palbociclib and the HIF-2α inhibitor showed significantly more cell-killing potential than either drug alone! Why would Palbociclib turn on HIF-2α in the first place? Lee and colleagues rounded off their study with some evidence that Palbociclib treatment induced the production of damaging molecular agents called reactive oxygen species (ROS), which may lead cells to turn on HIF-2α as part of a stress response.
While preclinical, these findings from Lee and colleagues firmly establish the therapeutic potential of Palbociclib—which has shown efficacy in an expanding collection of tumor types—in treating MCC. Furthermore, the finding that concurrent HIF-2α inhibition prevents PD-L1 induction and increases Palbociclib-induced cell death in MCC models is a striking example of how distinct treatments working in tandem can address each other’s limitations and result in a more potent cancer therapy. As Lee notes, “In this research, we found that concurrent Palbociclib treatment and HIF-2α inhibition can lead to a form of cell death called ferroptosis, which is immunogenic and thus recognized by the immune system. This suggests the exciting possibility that HIF-2α inhibition can not only prevent PD-L1-mediated immune suppression by Palbociclib, but also enhance anti-tumor immune responses by inducing immunogenic cell death. Connecting the intricate concepts of cell cycle regulation, immune suppression by PD-L1, and cellular redox stress/ferroptosis was challenging, but we’re excited to follow up on these results and see if they can lead to better treatments for MCC.”
The spotlighted work was funded by the National Institutes of Health, the Elsa U. Pardee Foundation, the MCC patient gift fund, and the Preclinical Modeling Core Laboratory Shared Resource of the Fred Hutch/University of Washington Cancer Consortium.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium members Drs. Aude Chapuis and Paul Nghiem and contributed to this study.
Lee, J. H., Lee, J. D., Paulson, K., Voillet, V., Berndt, A., Church, C., Lachance, K., Park, S. Y., Yamamoto, N. K., Cromwell, E. A., Gottardo, R., Chapuis, A. G., & Nghiem, P. (2024). Enhancing immunogenic responses through CDK4/6 and HIF2α inhibition in Merkel cell carcinoma. Heliyon, 10(1), e23521.