PT  - JOURNAL ARTICLE
AU  - Wang, Qingfei
AU  - Guldner, Ian H.
AU  - Golomb, Samantha M.
AU  - Sun, Longhua
AU  - Harris, Jack
AU  - Lu, Xin
AU  - Zhang, Siyuan
TI  - Single-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor resistant HER2-positive breast cancer
AID  - 10.1101/671198
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 671198
4099  - http://biorxiv.org/content/early/2019/06/14/671198.1.short
4100  - http://biorxiv.org/content/early/2019/06/14/671198.1.full
AB  - Development of acquired resistance to targeted cancer therapy is one of the most significant clinical challenges. Acquiring resistance under drug selection pressure is a result of evolutionary adaptation to a complex and dynamic tumor microenvironment (TME). New therapy regimens combining CDK4/6 inhibitor are under active investigation in clinical trials to treat HER2+ breast cancer patients. In parallel with clinical trial settings, in this study, we sought to prospectively model the tumor evolution in response to a targeted therapy regimen in vivo and identify a clinically actionable strategy to combat potential acquired resistance. Notably, despite a promising initial response, acquired resistance emerged rapidly to the anti-Her2/Neu antibody plus CDK4/6 inhibitor Palbociclib combination treatment. By leveraging high-throughput single-cell analyses of the evolving tumors over the course of treatments, we revealed a distinct immunosuppressive immature myeloid cell (IMC) population infiltrated in the resistant TME. Guided by single-cell transcriptome analysis, we demonstrated a combinatorial immunotherapy of IMC-targeting tyrosine kinase inhibitor cabozantinib and immune checkpoint blockades enhanced anti-tumor immunity, and overcame the resistance. Further, sequential combinatorial immunotherapy enabled a sustained control of the rapidly evolving CDK4/6 inhibitor-resistant tumors. Our study demonstrates a translational framework for treating rapidly evolving tumors through preclinical modeling and single-cell analyses. Our findings provide a rationale for an immediate clinical proposition of combinatorial immunotherapy for HER2+ breast cancer as a strategy to mitigate the emergence of resistance.