PIK3CA oncogenic mutations represent a major mechanism of resistance to trastuzumab in HER2/neu overexpressing uterine serous carcinomas

Authors

Jonathan D. Black, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA.
Salvatore Lopez, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA.
Emiliano Cocco, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA.
Stefania Bellone, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA.
Gary Altwerger, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA.
Carlton L. Schwab, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA.
Diana P. English, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA.
Elena Bonazzoli, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA.
Federica Predolini, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA.
Francesca Ferrari, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA.
Elena Ratner, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA.
Dan-Arin Silasi, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA.
Masoud Azodi, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA.
Peter E. Schwartz, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA.
Alessandro D. Santin, Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA.

Document Type

Article

Publication Title

British journal of cancer

Abstract

OBJECTIVES: We evaluated the role of PIK3CA-mutations as mechanism of resistance to trastuzumab in primary HER2/neu-amplified uterine-serous-carcinoma (USC) cell lines. METHODS: Fifteen whole-exome-sequenced USC cell lines were tested for HER2/neu-amplification and PIK3CA-mutations. Four HER2/neu-amplified USC (2-harbouring wild-type-PIK3CA-genes and 2-harbouring oncogenic-PIK3CA-mutations) were evaluated in in vitro dose-titration-proliferation-assays, cell-viability and HER2 and S6-protein-phosphorylation after exposure to trastuzumab. USC harbouring wild-type-PIK3CA were transfected with plasmids encoding oncogenic PIK3CA-mutations (i.e., H1047R/R93Q) and exposed to trastuzumab. Finally, trastuzumab efficacy was tested by using two USC xenograft mouse models. RESULTS: Seven out of fifteen (46%) of the USC cell lines were HER2/neu-amplified by fluorescence in situ hybridisation. Within these tumours four out of seven (57%) were found to harbour oncogenic PIK3CA-mutations vs two out of eight (25%) of the HER2/neu not amplified cell lines (P=0.01). HER2/neu-amplified/PIK3CA-mutated USC were highly resistant to trastuzumab when compared with HER2/neu-amplified/wild-type-PIK3CA cell lines (P=0.02). HER2/neu-amplified/PIK3CA wild-type cell lines transfected with oncogenic PIK3CA-mutations increased their resistance to trastuzumab (P<0.0001). Trastuzumab was effective in reducing tumour growth (P=0.001) and improved survival (P=0.0001) in mouse xenografts harbouring HER2-amplified/PIK3CA wild-type USC but not in HER2-amplified/PIK3CA-mutated tumours. CONCLUSIONS: Oncogenic PIK3CA mutations are common in HER2/neu-amplified USC and may constitute a major mechanism of resistance to trastuzumab treatment.

First Page

1020

Last Page

6

DOI

10.1038/bjc.2015.306

Publication Date

9-29-2015

Recommended Citation

Black, Jonathan D.; Lopez, Salvatore; Cocco, Emiliano; Bellone, Stefania; Altwerger, Gary; Schwab, Carlton L.; English, Diana P.; Bonazzoli, Elena; Predolini, Federica; Ferrari, Francesca; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E.; and Santin, Alessandro D., "PIK3CA oncogenic mutations represent a major mechanism of resistance to trastuzumab in HER2/neu overexpressing uterine serous carcinomas" (2015). Obstetrics and Gynecology. 162.
https://scholar.bridgeporthospital.org/obgyn/162

Identifier

26325104 (pubmed); PMC4651122 (pmc); 10.1038/bjc.2015.306 (doi); bjc2015306 (pii)