PI3K oncogenic mutations mediate resistance to afatinib in HER2/neu overexpressing gynecological cancers

被引：19

作者：

Bonazzoli, Elena ^{[1
]}

Cocco, Emiliano ^{[2
]}

Lopez, Salvatore ^{[1
,3
]}

Bellone, Stefania ^{[1
]}

Zammataro, Luca ^{[1
]}

Bianchi, Anna ^{[1
]}

Manzano, Aranzazu ^{[1
]}

Yadav, Ghanshyam ^{[1
]}

Manara, Paola ^{[1
]}

Perrone, Emanuele ^{[1
]}

Haines, Kaitlin ^{[1
]}

Espinal, Mariana ^{[1
]}

Dugan, Katherine ^{[1
]}

Menderes, Gulden ^{[1
]}

Altwerger, Gary ^{[1
]}

Han, Chanhee ^{[1
]}

Zeybek, Burak ^{[1
]}

Litkouhi, Babak ^{[1
]}

Ratner, Elena ^{[1
]}

Silasi, Dan-Arin ^{[1
]}

Huang, Gloria S. ^{[1
]}

Azodi, Masoud ^{[1
]}

Schwartz, Peter E. ^{[1
]}

Santin, Alessandro D. ^{[1
]}

机构：

[1] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT 06520 USA

[2] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[3] Magna Graecia Univ Catanzaro, Dept Expt & Clin Med, I-88100 Catanzaro, Italy

来源：

GYNECOLOGIC ONCOLOGY | 2019年 / 153卷 / 01期

关键词：

Gynecological cancer; Afatinib; PI3K mutation; Mechanism of resistance; HER2/neu overexpression; PHASE-II TRIAL; IN-VITRO; ACQUIRED-RESISTANCE; ENDOMETRIAL CANCER; UTERINE; CARCINOMA; TRASTUZUMAB; RECEPTOR; INHIBITOR; FAMILY;

D O I：

10.1016/j.ygyno.2019.01.002

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Objective. Aberrant expression of HER2/neu and PIK3CA gene products secondary to amplification/mutations are common in high-grade-serous-endometrial (USC) and ovarian-cancers (HGSOC). Because scant information is currently available in the literature on the potential negative effect of PIK3CA mutations on the activity of afatinib, in this study we evaluate for the first time the role of oncogenic PIK3CA mutations as a potential mechanism of resistance to afatinib in HGSOC and USC overexpressing HER2/neu. Methods. We used six whole-exome-sequenced primary HGSOC/USC cell-lines and three xenografts overexpressing HER2/neu and harboring mutated or wild-type PIK3CA/PIK3R1 genes to evaluate the role of PI3K-mutations as potential mechanism of resistance to afatinib, an FDA-approved pan-c-erb-inhibitor in clinical trials in USC. Primary-USC harboring wild-type-PIK3CA gene was transfected with plasmids encoding oncogenic PIK3CA-mutations (H1047R/E545K). The effect of afatinib on HER2/PI3K/AKT/mTOR pathway was evaluated by immunoblotting. Results. We found PI3K wild-type cell-lines to be significantly more sensitive (lower IC50) than PI3K-mutated cell-lines p = 0.004). In vivo, xenografts of primary cell-line USC-ARK2, transfected with the PIK3CA-H1047R or E545K hotspot-mutations, exhibited significantly more rapid tumor growth when treated with afatinib, compared to mice harboring ARK2-tumors transfected with wild-type-PIK3CA (p = 0.041 and 0.001, respectively). By western-blot, afatinib effectively reduced total and phospho-HER2 proteins in all cell-lines. However, H1047R/E545K-PIK3CA-transfected-ARK2-cells demonstrated a greater compensatory increase in phosphorylated-AICT proteins after afatinib exposure when compared to controls ARK2. Conclusions. Oncogenic PI3K mutations may represent a major mechanism of resistance to afatinib. Combinations of c-erb with PIK3CA, AKT or mTOR inhibitors may be necessary to more efficiently block the PIK3CA/AKT/mTOR pathway. (C) 2019 Elsevier Inc. All rights reserved.

引用

页码：158 / 164

页数：7

共 41 条

[41] Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma [J].

Zhao, Siming ;

Choi, Murim ;

Overton, John D. ;

Bellone, Stefania ;

Roque, Dana M. ;

Cocco, Emiliano ;

Guzzo, Federica ;

English, Diana P. ;

Varughese, Joyce ;

Gasparrini, Sara ;

Bortolomai, Ileana ;

Buza, Natalia ;

Hui, Pei ;

Abu-Khalaf, Maysa ;

Ravaggi, Antonella ;

Bignotti, Eliana ;

Bandiera, Elisabetta ;

Romani, Chiara ;

Todeschini, Paola ;

Tassi, Renata ;

Zanotti, Laura ;

Carrara, Luisa ;

Pecorelli, Sergio ;

Silasi, Dan-Arin ;

Ratner, Elena ;

Azodi, Masoud ;

Schwartz, Peter E. ;

Rutherford, Thomas J. ;

Stiegler, Amy L. ;

Mane, Shrikant ;

Boggon, Titus J. ;

Schlessinger, Joseph ;

Lifton, Richard P. ;

Santin, Alessandro D. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (08) :2916-2921

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