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

By Benjamin G Neel, Chewei Anderson Chang, Shaowen Jiang, Azin Sayad, Kevin R. Brown, Allison Nixon, Avantika Dhabaria, Kwan Ho Tang, Jason Moffat, Beatrix Ueberheide, Alireza Khodadadi-Jamayran, Aristotelis Tsirigos

Posted 28 Aug 2020
bioRxiv DOI: 10.1101/2020.08.28.273029

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.

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