Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 57,773 bioRxiv papers from 265,845 authors.
Single-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor resistant HER2-positive breast cancer
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.
- Downloaded 425 times
- Download rankings, all-time:
- Site-wide: 21,260 out of 57,773
- In cancer biology: 642 out of 1,870
- Year to date:
- Site-wide: 4,750 out of 57,773
- Since beginning of last month:
- Site-wide: 4,040 out of 57,773
Downloads over time
Distribution of downloads per paper, site-wide
- Top preprints of 2018
- Paper search
- Author leaderboards
- Overall metrics
- The API
- Email newsletter
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!