Open AccessTargeting HER 2 in patient‐derived xenograft ovarian cancer models sensitizes tumors to chemotherapy
Author(s) -
Harris Faye R.,
Zhang Piyan,
Yang Lin,
Hou Xiaonan,
Leventakos Konstantinos,
Weroha Saravut J.,
Vasmatzis George,
Kovtun Irina V.
Publication year - 2019
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12414
Subject(s) - ovarian cancer , carboplatin , paclitaxel , medicine , chemotherapy , pertuzumab , cancer research , oncology , erbb , cancer , olaparib , cisplatin , trastuzumab , breast cancer , biology , gene , biochemistry , polymerase , poly adp ribose polymerase
Ovarian cancer is the most lethal gynecologic malignancy. About 75% of ovarian cancer patients relapse and/or develop chemo‐resistant disease after initial response to standard‐of‐care treatment with platinum‐based therapies. HER 2 amplifications and overexpression in ovarian cancer are reported to vary, and responses to HER 2 inhibitors have been poor. Next generation sequencing technologies in conjunction with testing using patient‐derived xenografts ( PDX ) allow validation of personalized treatments. Using a whole‐genome mate‐pair next generation sequencing ( MP seq) protocol, we identified several high grade serous ovarian cancers ( HGS ‐ OC ) with DNA alterations in genes encoding members of the ERBB 2 pathway. The efficiency of anti‐ HER 2 therapy was tested in three different PDX lines with the identified alterations and high levels of HER 2 protein expression. Treatment responses to pertuzumab or pertuzumab/trastuzumab were compared in each PDX line WITH standard carboplatin and paclitaxel combination treatment. In all three PDX models, HER 2‐targeted therapy resulted in significant inhibition of tumor growth compared with untreated controls. However, the responses in each case were inferior to those to chemotherapy, even for chemo‐resistant lines. When chemotherapy and HER 2‐targeted therapy were administered together, a significant regression of tumor was observed after 6 weeks of treatment compared with chemotherapy alone. Post‐treatment analysis of these tissues revealed that inhibition of the ERBB 2 pathway occurred at the level of phosphorylation and expression of downstream targets. In conclusion, while targeting of presumably activated ERBB 2 pathway alone in HGS ‐ OC results in a modest treatment benefit, a combination therapy including both chemotherapy drugs and HER 2 inhibitors provides a far better response. Further studies are needed to address development of recurrence and sensitivity of recurrent disease to HER 2‐targeted therapy.