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Discov Med. 2018 Aug;26(141):39-50.

Mechanisms of resistance to HER2-targeted therapies in HER2-amplified uterine serous carcinoma, and strategies to overcome it.

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Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, 88100, Italy.
Gynecologic Oncology, Saint Peter's Physician Associates, New Brunswick, NJ 08901, USA.


Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that accounts for up to 40% of all endometrial cancer-related deaths. Recent whole-exome sequencing studies have revealed HER2/neu amplification in 27-44% of USC patients, supporting HER2 as an attractive pathway for target therapies based on monoclonal antibodies or tyrosine kinase inhibitors. Preclinical studies and a recently published prospective randomized trial with trastuzumab in combination with chemotherapy demonstrated promising results with anti-HER2-targeted therapies in advanced and recurrent USC patients. In contrast, single-agent trastuzumab or tyrosine kinase inhibitors (i.e., lapatinib) were unable to demonstrate significant clinical activity and/or durable tumor growth inhibition. Combinatorial therapies may represent novel, highly effective therapeutic strategies to overcome inborn or acquired resistance to HER2/neu-targeted therapies in HER2-amplified USC patients. This study presents a comprehensive review of the mechanisms of USC resistance to HER2-targeted therapies and potential strategies to overcome it.

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