Whole-exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy

Luca Zammataro, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Salvatore Lopez, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Stefania Bellone, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Francesca Pettinella, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Elena Bonazzoli, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Emanuele Perrone, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Siming Zhao, Department of Human Genetics, The University of Chicago, Chicago, IL 60637.
Gulden Menderes, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Gary Altwerger, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Chanhee Han, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Burak Zeybek, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Anna Bianchi, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Aranzazu Manzano, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Paola Manara, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Emiliano Cocco, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Natalia Buza, Department of Pathology, Yale University School of Medicine, New Haven, CT 06520.
Pei Hui, Department of Pathology, Yale University School of Medicine, New Haven, CT 06520.
Serena Wong, Department of Pathology, Yale University School of Medicine, New Haven, CT 06520.
Antonella Ravaggi, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics, & Gynecology, University of Brescia, 25100 Brescia, Italy.
Eliana Bignotti, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics, & Gynecology, University of Brescia, 25100 Brescia, Italy.
Chiara Romani, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics, & Gynecology, University of Brescia, 25100 Brescia, Italy.
Paola Todeschini, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics, & Gynecology, University of Brescia, 25100 Brescia, Italy.
Laura Zanotti, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics, & Gynecology, University of Brescia, 25100 Brescia, Italy.
Franco Odicino, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics, & Gynecology, University of Brescia, 25100 Brescia, Italy.
Sergio Pecorelli, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics, & Gynecology, University of Brescia, 25100 Brescia, Italy.
Carla Donzelli, Department of Pathology, University of Brescia, 25100 Brescia, Italy.
Laura Ardighieri, Department of Pathology, University of Brescia, 25100 Brescia, Italy.
Roberto Angioli, Department of Gynecology and Obstetrics, Università Campus Bio-Medico di Roma, 00128 Rome, Italy.
Francesco Raspagliesi, Department of Gynecology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori di Milano, 20133 Milan, Italy.
Giovanni Scambia, Institute of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
Jungmin Choi, Department of Genetics, The Rockefeller University, New York, NY 10065.
Weilai Dong, Department of Genetics, The Rockefeller University, New York, NY 10065.

Document Type

Article

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

Abstract

The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cervical cancer cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most of which harboring Human-Papillomavirus-type-16/18. We found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, and GNAS) and a widespread APOBEC cytidine deaminase mutagenesis pattern (TCW motif) in both adenocarcinoma (ACC) and squamous cell carcinomas (SCCs). Somatic copy number variants (CNVs) identified 12 copy number gains and 40 losses, occurring more often than expected by chance, with the most frequent events in pathways similar to those found from analysis of single nucleotide variants (SNVs), including the ERBB2/PI3K/AKT/mTOR, apoptosis, chromatin remodeling, and cell cycle. To validate specific SNVs as targets, we took advantage of primary cervical tumor cell lines and xenografts to preclinically evaluate the activity of pan-HER (afatinib and neratinib) and PIK3CA (copanlisib) inhibitors, alone and in combination, against tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway (71%). Tumors harboring ERBB2 (5.8%) domain mutations were significantly more sensitive to single agents afatinib or neratinib when compared to wild-type tumors in preclinical in vitro and in vivo models (P = 0.001). In contrast, pan-HER and PIK3CA inhibitors demonstrated limited in vitro activity and were only transiently effective in controlling in vivo growth of PIK3CA-mutated cervical cancer xenografts. Importantly, combinations of copanlisib and neratinib were highly synergistic, inducing long-lasting regression of tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway. These findings define the genetic landscape of cervical cancer, suggesting that a large subset of cervical tumors might benefit from existing ERBB2/PIK3CA/AKT/mTOR-targeted drugs.

First Page

22730

Last Page

22736

DOI

10.1073/pnas.1911385116

Publication Date

11-5-2019

Identifier

31624127 (pubmed); PMC6842590 (pmc); 10.1073/pnas.1911385116 (doi); 1911385116 (pii)

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