Investigating SIX1 as a driver and target for a first in-class EMT degrader in head-and-neck squamous cell carcinoma

Prognosis for head-and-neck squamous cell carcinoma (HNSCC) remains poor in advanced stages, and patients suffer from severe treatment-associated adverse effects. Here, we have preliminarily investigated whether the embryonic transcription factor SIX1 drives HNSCC and could serve as a target for a first-in-class EMT degrader. While SIX1 is required during embryonic development, it is no longer or only weakly expressed in adult tissue. However, many cancers show a reactivation of SIX1, leading to various pro-tumorigenic effects such as an increase in proliferation and an induction of epithelial-mesenchymal transition (EMT). This makes SIX1, particularly combined with its absent or low expression in normal tissue, a potentially therapeutic target. For this purpose, we developed a SIX1-specific PROTAC (ELX19) through a CRO. In this project, we have applied sequential immunofluorescence for the analysis of patient tissue, and in vitro assays to test the efficiency of the SIX1 degradation through ELX19 and detect associated phenotypic effects. The 36-marker immunofluorescence panel confirmed an increased SIX1 expression in cancer tissue and showed a correlation between SIX1 and an immunosuppressive immune infiltrate, highlighting potential mechanistic links between SIX1 and HNSC progression. Regarding the PROTAC, ELX19 led to an efficient SIX1 degradation in the nanomolar and low micromolar range (depending on the cell line) and induced therapeutically desirable effects, such as an increase in apoptosis under cisplatin. In conclusion, these preliminary results indicate the potential of SIX1 as a therapeutic option in HNSCC - an option that patients urgently need.