Single-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor-resistant HER2-positive breast cancer

Qingfei Wang (), Ian H. Guldner, Samantha M. Golomb, Longhua Sun, Jack A. Harris, Xin Lu and Siyuan Zhang ()
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Qingfei Wang: University of Notre Dame
Ian H. Guldner: University of Notre Dame
Samantha M. Golomb: University of Notre Dame
Longhua Sun: University of Notre Dame
Jack A. Harris: University of Notre Dame
Xin Lu: University of Notre Dame
Siyuan Zhang: University of Notre Dame

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11729-1

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