Article Published: 03 June 2021Serial single-cell genomics reveals convergent subclonal evolution of resistance as patients with early-stage breast cancer progress on endocrine plus CDK4
Trang 1Article Published: 03 June 2021
Serial single-cell genomics reveals convergent subclonal evolution
of resistance as patients with early-stage breast cancer progress
on endocrine plus CDK4/6 therapy
Jason I Griffiths, Jinfeng Chen, Patrick A Cosgrove, Anne O’Dea, Priyanka Sharma, Cynthia Ma,
Meghna Trivedi, Kevin Kalinsky, Kari B Wisinski, Ruth O’Regan, Issam Makhoul, Laura M Spring,
Aditya Bardia, Frederick R Adler, Adam L Cohen, Jeffrey T Chang, Qamar J Khan & Andrea H.
using single-cell RNA sequencing of serial biopsies from the FELINE clinical trial of endocrinetherapy (letrozole) alone or combined with the CDK inhibitor ribociclib Despite differences insubclonal diversity evolution across patients and treatments, common resistance phenotypes
emerged Resistant tumors treated with combination therapy showed accelerated loss of estrogensignaling with convergent upregulation of JNK signaling through growth factor receptors In
contrast, cancer cells maintaining estrogen signaling during mono- or combination therapy
showed potentiation of CDK4/6 activation and ERK upregulation through ERBB4 signaling
These results indicate that combination therapy in early-stage estrogen receptor-positive breast
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Trang 2cancer leads to emergence of resistance through a shift from estrogen to alternative growth mediated proliferation.
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Data availability
Raw single-cell RNA-seq data are available through Gene Expression Omnibus under accession
provided with this manuscript as individual Excel files (one per figure) and listed in the Inventory.Code for Figs 1–6 is available on our GitHub repository at
https://elkssl99cd2175108d157588c04758296d1cfcelksslnature.casb.nju.edu.cn:4443/U54Bioinformatics/FELINE_project All other data supporting the findings of this study are available fromthe corresponding author on reasonable request Source data are provided with this paper
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Acknowledgements
We thank the anonymous patients from the trial that made this study possible A.H.B., J.G., J.C.,J.T.C., P.C and F.A were supported by the National Cancer Institute of the National Institutes ofHealth (NIH) under award number U54CA209978 The content is solely the authors
responsibility and does not necessarily represent the official views of the NIH The
High-Throughput Genomics Shared Resource was supported by the NIH award number P30CA042014.The Integrative Genomics Core was supported by NIH award number P30CA33572 J.T.C was
Trang 12supported by a Cancer Prevention Research Institute of Texas Core Facility Support Award
(RP170668)
Author information
1 Jinfeng Chen
Present address: State Key Laboratory of Integrated Management of Pest Insects and
Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
2 These authors contributed equally: Jason I Griffiths, Jinfeng Chen
3 These authors jointly supervised this work: Andrea H Bild, Qamar J Khan
Affiliations
1 Department of Medical Oncology and Therapeutics Research, City of Hope National
Medical Center, Duarte, CA, USA
Jason I Griffiths, Jinfeng Chen, Patrick A Cosgrove & Andrea H Bild
2 Department of Mathematics, University of Utah, Salt Lake City, UT, USA
Jason I Griffiths & Frederick R Adler
3 Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, USA
Anne O’Dea, Priyanka Sharma & Qamar J Khan
4 Division of Oncology, Washington University School of Medicine, St Louis, MO, USA
Cynthia Ma