Inhibition of CDKs Enhances Efficacy of Anti-EGFR Therapy in Chordoma

Abstract Abstract In chordoma, epidermal growth factor receptor (EGFR) blockade shows significant but incomplete anti-tumor activity, suggesting that inhibition of other tumor growth promoting pathways is required for enhanced efficacy. Here, we detected high expression of cyclin-dependent kinase (CDK) 7 and 9 in both sacral and clival chordomas, and subsequently explored the efficacy of the CDKs inhibitors THZ1 and TG02, both as single agents and in combination with EGFR inhibitor afatinib in preclinical chordoma models. Monotherapy with THZ1, TG02, and afatinib led to decreased cell viability, proliferative capacity, colony formation and induced cell apoptosis across multiple chordoma cell lines, and enhanced activity was observed with THZ1/afatinib and TG02/afatinib co-treatments. Mechanistically, THZ1 and TG02 attenuated phosphorylation of POL II, leading to transcriptional inhibition of the chordoma driver gene brachyury, which was enhanced when combined with afatinib. Both CDK inhibitors also reduced expression of MCL1 which was further suppressed with combination therapy. Importantly, co-treatments exhibited greater inhibition of tumor growth than single treatments in cell line- and patient-derived xenograft models. Taken together, our data revealed that THZ1 or TG02 enhanced in vitro and in vivo efficacy of afatinib, suggesting a potential novel combination therapeutic strategy for patients with chordoma.