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Cancer Drug Resist 2022;5:[Accepted].10.20517/cdr.2022.48© The Author(s) 2022
Accepted Manuscript
Open AccessReview

Mechanisms of neratinib resistance in HER2-mutant metastatic breast cancer 

Correspondence Address: Dr. Lisa D. Eli, Translational Medicine and Diagnostics, Puma Biotechnology, Inc., 10880 Wilshire Blvd, Suite 150, Los Angeles, CA, 90024, USA. E-mail:; Dr. Shyam. M. Kavuri, Lester and Sue Smith Breast Center and Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. E-mail:


© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (, which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.


Human epidermal growth factor receptor 2 (HER2) is a major drug target and clinical biomarker in breast cancer treatment. Targeting HER2 gene amplification is one of the greatest successes in oncology, resulting in the use of a wide array of HER2-directed agents in the clinic. The discovery of HER2-activating mutations as novel therapeutic targets in breast and other cancers marked a significant advance in the field, which led to the metastatic breast and other solid tumor trials MutHER (NCT01670877), SUMMIT (NCT01953926), and one arm of plasmaMATCH (NCT03182634). These trials have reported initial clinical benefit followed by eventual relapse ascribed to either primary or acquired resistance. These resistance mechanisms are mediated by additional secondary genomic alterations within HER2 itself and via hyperactivation of oncogenic signaling within the downstream signaling axis. 

Cite This Article

Eli LD, Kavuri SM. Mechanisms of neratinib resistance in HER2-mutant metastatic breast cancer. Cancer Drug Resist 2022;5:[Accept].

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