Anlotinib enhances the sensitivity to docetaxel in lung cancer through inhibiting DDR1-mediated glycolytic pathway

Abstract

Discoidin domain receptor 1 (DDR1), a collagen-activated receptor tyrosine kinase, is essential for tumor cell proliferation, invasion and drug resistance. Our study demonstrated that the expression and phosphorylation of DDR1 were associated not only with the poor outcome of non-small cell lung cancer (NSCLC), but also with low sensitivity to docetaxel. Moreover, our kinase profiling identified that anlotinib, an oral small-molecule tyrosine kinase inhibitor, could significantly inhibit DDR1 phosphorylation. Further data revealed that anlotinib could increase the sensitivity to docetaxel in cell lines, cell-derived and patient-derived tumor xenografts through down-regulating DDR1 phosphorylation, which no longer existed in DDR1-KO A549 cells. Mechanistically, anlotinib could enhance the sensitivity to docetaxel through inhibiting DDR1-mediated glycolysis. Additionally, the clinical trial demonstrated that anlotinib could increase the efficacy of docetaxel, with an improved overall response rate of 35.6%, a prolonged median progression-free survival by 5.3 months and a median overall survival by 14.0 months compared with historical data. In summary, our study not only highlights the new function of DDR1 in energy metabolism but also provides further evidence for the combination of anlotinib and docetaxel as a preferable strategy in clinical practice.