Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer

Nindo B. Punturi, Sinem Seker, Vaishnavi Devarakonda, Aloran Mazumder, Rashi Kalra, Ching Hui Chen, Shunqiang Li, Tina Primeau, Matthew J. Ellis, Shyam M. Kavuri () and Svasti Haricharan ()
Additional contact information
Nindo B. Punturi: Sanford Burnham Prebys Medical Discovery Institute
Sinem Seker: Sanford Burnham Prebys Medical Discovery Institute
Vaishnavi Devarakonda: Baylor College of Medicine
Aloran Mazumder: Sanford Burnham Prebys Medical Discovery Institute
Rashi Kalra: Baylor College of Medicine
Ching Hui Chen: Baylor College of Medicine
Shunqiang Li: Washington University in St. Louis
Tina Primeau: Washington University in St. Louis
Matthew J. Ellis: Baylor College of Medicine
Shyam M. Kavuri: Baylor College of Medicine
Svasti Haricharan: Sanford Burnham Prebys Medical Discovery Institute

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Resistance to endocrine treatment occurs in ~30% of ER+ breast cancer patients resulting in ~40,000 deaths/year in the USA. Preclinical studies strongly implicate activation of growth factor receptor, HER2 in endocrine treatment resistance. However, clinical trials of pan-HER inhibitors in ER+/HER2− patients have disappointed, likely due to a lack of predictive biomarkers. Here we demonstrate that loss of mismatch repair activates HER2 after endocrine treatment in ER+/HER2− breast cancer cells by protecting HER2 from protein trafficking. Additionally, HER2 activation is indispensable for endocrine treatment resistance in MutL- cells. Consequently, inhibiting HER2 restores sensitivity to endocrine treatment. Patient data from multiple clinical datasets supports an association between MutL loss, HER2 upregulation, and sensitivity to HER inhibitors in ER+/HER2− patients. These results provide strong rationale for MutL loss as a first-in-class predictive marker of sensitivity to combinatorial treatment with endocrine intervention and HER inhibitors in endocrine treatment-resistant ER+/HER2− breast cancer patients.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-23271-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23271-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-23271-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().