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

Qingfei Wang,Jack A Harris,Xin Lu,Ian H Guldner,Siyuan Zhang,Samantha M Golomb,Longhua Sun

doi:10.1038/s41467-019-11729-1

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.

Highlights

Acquired resistance to targeted cancer therapy is a significant clinical challenge
Control mice exhibited an average of 108.4% increase in tumor size over the same period, and Pal or Ab single treatment only showed a mild to moderate effect
One exception to the seemingly mutually exclusive clustering based on treatment was cluster 4, which was characterized by the high expression of proliferation genes such as Top2a, Cdk[1], Mki[67], and Cenpa (Supplementary Fig. 2D), suggesting that subpopulation of tumor cells conferred tolerance to treatment or adapted to drug selection

Summary

Introduction

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. Targeting cyclin D1-CDK4 acts synergistically with trastuzumab and, more intriguingly, elicits anti-tumor immune response[33,34] In light of such strong preclinical evidence and together with the recent advance of CDK4/6 inhibitors for estrogen receptor (ER)-positive breast cancer[35,36], new combinatorial regimen of CDK4/6 inhibitors plus trastuzumab is under active clinical investigation[37,38]. Our rationally designed sequential combinatorial regimens enable a durable response and sustained control of the emergence of acquired resistance in rapidly evolving HER2-positive breast cancers

Methods

Results

Conclusion