Wang, QingfeiGuldner, Ian H.Golomb, Samantha M.Sun, LonghuaHarris, Jack A.Lu, XinZhang, Siyuan2019-10-102019-10-102019-08-23Wang, Q., Guldner, I. H., Golomb, S. M., Sun, L., Harris, J. A., Lu, X., & Zhang, S. (2019). Single-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor-resistant HER2-positive breast cancer. Nature communications, 10(1), 3817. doi:10.1038/s41467-019-11729-1https://hdl.handle.net/1805/21100Acquired resistance to targeted cancer therapy is a significant clinical challenge. In parallel with clinical trials combining CDK4/6 inhibitors to treat HER2+ breast cancer, we sought to prospectively model tumor evolution in response to this regimen in vivo and identify a clinically actionable strategy to combat drug resistance. Despite a promising initial response, acquired resistance emerges rapidly to the combination of anti-HER2/neu antibody and CDK4/6 inhibitor Palbociclib. Using high-throughput single-cell profiling over the course of treatments, we reveal a distinct immunosuppressive immature myeloid cell (IMC) population to infiltrate the resistant tumors. Guided by single-cell transcriptome analysis, we demonstrate that combination of IMC-targeting tyrosine kinase inhibitor cabozantinib and immune checkpoint blockade enhances anti-tumor immunity, and overcomes the resistance. Furthermore, sequential combinatorial immunotherapy enables a sustained control of the fast-evolving CDK4/6 inhibitor-resistant tumors. Our study demonstrates a translational framework for treating rapidly evolving tumors through preclinical modeling and single-cell analyses.en-USAttribution 4.0 United StatesRNA sequencingCancer microenvironmentArticle