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

Abstract In chordoma, epidermal growth factor receptor (EGFR) blockade shows significant but incomplete antitumor activity, suggesting that inhibition of other tumor growth–promoting pathways is required for enhanced efficacy. In this study, we detected high expression of cyclin-dependent kinases (CDKs), specifically CDK7 and CDK9, in both sacral and clival chordomas and subsequently explored the efficacy of the CDK inhibitors THZ1 and TG02, both as single agents and in combination with the EGFR inhibitor afatinib in preclinical chordoma models. Monotherapy with THZ1, TG02, and afatinib led to decreased cell viability, proliferative capacity, colony formation, and induced apoptosis across multiple chordoma cell lines, and enhanced activity was observed with THZ1/afatinib and TG02/afatinib cotreatments. Mechanistically, THZ1 and TG02 each attenuated phosphorylation of RNA polymerase 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, cotreatments 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 the in vitro and in vivo efficacy of afatinib, suggesting a potential novel combination therapeutic strategy for patients with chordoma.