Ontogeny and Vulnerabilities of Lapatinib Drug-Tolerant Persisters in HER2+ Breast Cancer
Benjamin G Neel,
Chewei Anderson Chang,
Kevin R. Brown,
Kwan Ho Tang,
Posted 28 Aug 2020
bioRxiv DOI: 10.1101/2020.08.28.273029
Posted 28 Aug 2020
Despite advances in targeted therapeutics, resistance remains a significant clinical problem in HER2-positive (HER2+) breast cancer and can lead to recurrence, metastasis, and death. Drug- tolerant persisters (DTPs), a sub-population of cancer cells that survive via reversible, non- genetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKIs) in several cancer models, but DTPs following HER2 TKIs exposure have not been characterized extensively. We found that treatment of HER2+ breast cancer lines with lapatinib evoked DTPs with either a luminal-like or a mesenchymal-like transcriptional program and differential sensitivity to lapatinib/anti-estradiol combinations. Lentiviral barcoding and single cell RNA-sequencing showed that luminal-like HER2+ cells cycle stochastically through a pre-DTP state, characterized by a G0-like signature, which uniquely gives rise to DTPs upon lapatinib exposure. Lapatinib-DTPs from luminal-like HER2+ cells survive via estrogen receptor-dependent induction of SGK3, thereby rewiring their PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation. These results provide new insights into DTP ontogeny and therapeutic vulnerabilities. ### Competing Interest Statement B.G.N. is a co-founder, holds equity in, and receives consulting fees from Navire Pharmaceuticals and Northern Biologics, Inc. He is a member of the Scientific Advisory Board and receives consulting fees and equity from Avrinas, Inc, and was an expert witness for the Johnson and Johnson ovarian cancer talc litigation in US Federal Court. His spouse has or held equity in Amgen, Inc., Regeneron, Moderna, Inc., Gilead Sciences, Inc., and Arvinas, Inc. J.M. is a shareholder in Northern Biologics and Pionyr Immunotherapeutics and is an advisor and shareholder of Century Therapeutics and Aelian Biotechnology.
- Downloaded 210 times
- Download rankings, all-time:
- Site-wide: 78,939 out of 103,809
- In cancer biology: 2,687 out of 3,707
- Year to date:
- Site-wide: 30,145 out of 103,809
- Since beginning of last month:
- Site-wide: 16,781 out of 103,809
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 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!