Wang, Guldner, Golomb, Sun, Harris, Lu, Zhang (2019) Single-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor-resistant HER2-positive breast cancer Nature communications 10(1) 3817

Abstract

Acquired 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.

Links

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707314/pdf/
http://www.ncbi.nlm.nih.gov/pubmed/31444334
http://dx.doi.org/10.1038/s41467-019-11729-1

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