Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. "Drug-tolerant persisters" (DTP), a subpopulation of cancer cells that survive via reversible, nongenetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKI) i...

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Published inCancer discovery Vol. 12; no. 4; pp. 1022 - 1045
Main Authors Chang, Chewei Anderson, Jen, Jayu, Jiang, Shaowen, Sayad, Azin, Mer, Arvind Singh, Brown, Kevin R, Nixon, Allison M L, Dhabaria, Avantika, Tang, Kwan Ho, Venet, David, Sotiriou, Christos, Deng, Jiehui, Wong, Kwok-Kin, Adams, Sylvia, Meyn, Peter, Heguy, Adriana, Skok, Jane A, Tsirigos, Aristotelis, Ueberheide, Beatrix, Moffat, Jason, Singh, Abhyudai, Haibe-Kains, Benjamin, Khodadadi-Jamayran, Alireza, Neel, Benjamin G
Format Journal Article
LanguageEnglish
Published United States 01.04.2022
Subjects
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Cell Line, Tumor
Drug Resistance, Neoplasm
Female
Humans
Phosphatidylinositol 3-Kinases - metabolism
Receptor, ErbB-2 - genetics
Receptor, ErbB-2 - metabolism
Signal Transduction
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Summary:Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. "Drug-tolerant persisters" (DTP), a subpopulation of cancer cells that survive via reversible, nongenetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKI) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single-cell RNA sequencing reveals that HER2+ breast cancer cells cycle stochastically through a "pre-DTP" state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting shows that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor-dependent induction of SGK3, leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation. DTPs are implicated in resistance to anticancer therapies, but their ontogeny and vulnerabilities remain unclear. We find that HER2 TKI-DTPs emerge from stochastically arising primed cells ("pre-DTPs") that engage either of two distinct transcriptional programs upon TKI exposure. Our results provide new insights into DTP ontogeny and potential therapeutic vulnerabilities. This article is highlighted in the In This Issue feature, p. 873.
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These authors contributed equally.
C.A.C. and B.G.N. conceptualized the study. C.A.C., J.M., J.J., and B.G.N. designed the experiments. C.A.C. performed the majority of the initial experiments. J.J. performed most of the experiments for the revision. A.S.M. and B.H. performed expression analysis of the NeoALTTO trial data. D.V. and C.S. provided data from this trial. S.J., A.S., K.R.B., A.K. and A.T. performed bioinformatics analysis. A.N., J.J. J.M. performed the DNA barcode amplifications and sequencing. A.H. and P.M. helped design and perform genomics analyses. A.D. and B.U. performed the mass spectrometry experiments and analyses. K.H.T. performed the mammary fat-pad injections for the limiting dilution assay. C.A.C. and B.G.N. wrote the manuscript, which all authors helped to edit. J.D., K.K.W. and S.A. provided primary HER2 and TN breast tumor scRNA-seq datasets.
Author Contributions
Present address: AbbVie, South San Francisco, CA, USA.
ISSN:2159-8274
2159-8290
2159-8290
DOI:10.1158/2159-8290.cd-20-1265