Novel SOX2-targeting bioPROTACs as multi-faceted anti-tumor agents overcoming resistance to standard therapies in lung cancers

SOX2 is one of the pluripotency transcription factors and has been well-known for its crucial role in tumor development through promoting cancer cell survival, metastasis, stemness, and drug resistance. Numerous studies have reported the overexpression of SOX2 in various tumor tissues, such as ovarian, esophageal, and head and neck cancers, and demonstrated an associated poor prognosis. Thus, SOX2 has emerged as a therapeutic target for anti-tumor agents, but directly targeting SOX2 has been proven to be difficult since SOX2 is an “undruggable” transcription factor. Here, we show the versatile anti-tumor efficacy of our SOX2 bioPROTACs as first-in-class SOX2 degraders. Our SOX2 bioPROTACs are composed of a nanobody against SOX2 with high affinity and modified E3 ligases with deletion of natural substrate binding domain, which in turn achieve highly selective degradation of SOX2 protein. First, we validated the potent SOX2 protein degradation and therapeutic efficacy of SOX2 bioPROTACs in lung squamous cell carcinoma (LUSC) cells, which present difficulties for targeted therapy due to the lack of common oncogenic driver mutations. Given that SOX2 is amplified in about 40% of LUSC patients, our SOX2 bioPROTACs offer a promising alternative for patients currently lacking effective therapeutic options. In addition, we confirmed SOX2 overexpression in several chemo-resistant cell lines, and subsequently demonstrated that SOX2 bioPROTACs exhibit synergistic efficacy in combination with chemotherapy via SOX2 degradation. We also verified remarkable tumor growth inhibition in chemo-resistant patient-derived xenograft models upon co-treatment with SOX2 bioPROTACs and chemotherapy, thereby firmly establishing their potential to bypass existing drug resistance. Notably, diverse EGFR-TKIs induced elevated SOX2 levels in EGFR-mutant lung cancer cells and we found that the combination of SOX2 bioPROTACs and EGFR-TKIs resulted in a significant improvement in therapeutic efficacy compared to EGFR-TKI alone. Furthermore, the induction level of SOX2 by EGFR-TKIs was much higher than that of ADC targets, such as TROP2, HER2, or MET, which are actively being developed for combination therapy to overcome EGFR-TKI resistance. This suggests the potential superiority of our SOX2 bioPROTACs as a combination partner for EGFR-TKIs. Finally, we developed the clinically applicable drug product by utilizing a lung-targeted lipid nanoparticle (LNP), and confirmed its potent anti-tumor efficacy upon intravenous injection into an orthotopic lung cancer model. Taken together, our novel SOX2 bioPROTACs exert superior anti-tumor efficacy through multi-faceted mechanisms, positioning them as optimal therapeutic candidates for patients who face challenges in treatment due to the limitations of existing therapies.