Targeting HER2 in patient‐derived xenograft ovarian cancer models sensitizes tumors to chemotherapy

Abstract

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. HER2 amplifications and overexpression in ovarian cancer are reported to vary, and responses to HER2 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 (MPseq) protocol, we identified several high grade serous ovarian cancers (HGS‐OC) with DNA alterations in genes encoding members of the ERBB2 pathway. The efficiency of anti‐HER2 therapy was tested in three different PDX lines with the identified alterations and high levels of HER2 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, HER2‐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 HER2‐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 ERBB2 pathway occurred at the level of phosphorylation and expression of downstream targets. In conclusion, while targeting of presumably activated ERBB2 pathway alone in HGS‐OC results in a modest treatment benefit, a combination therapy including both chemotherapy drugs and HER2 inhibitors provides a far better response. Further studies are needed to address development of recurrence and sensitivity of recurrent disease to HER2‐targeted therapy.

Current Status of Patient-Derived Ovarian Cancer Models

“…Hedgehog pathway, upregulated in a subset of OC [58], was also targeted with a specific inhibitor, leading to significant decrease of tumor volume in OC PDX [59]. More recently, combinatorial therapy including both chemotherapeutic agents and HER2 inhibitors was evaluated on OC PDX [60]. Furthermore, tumorigenicity as xenografts per se proved to be inversely correlated with progression-free survival [61].…”

Nrf2 Inhibitor, Brusatol in Combination with Trastuzumab Exerts Synergistic Antitumor Activity in HER2-Positive Cancers by Inhibiting Nrf2/HO-1 and HER2-AKT/ERK1/2 Pathways

“…Therefore, more effective targeted-therapy strategies for HER2-positive cancers are necessary to overcome the limitation of trastuzumab in efficacy. Harris et al found that single-agent trastuzumab results in a limited treatment benefit in ovarian cancers; however, a combination therapy including both chemotherapy drugs and HER2-targeted antibody provides a far better response [ 43 ]. Many studies have also indicated that new combinatorial regimens of trastuzumab with other antibodies or small-molecule inhibitors may contribute to enhance the efficacy of trastuzumab and overcome trastuzumab resistance [ 9 , 44 , 45 ].…”

Patient-derived bladder cancer xenograft models reveal VEGF and CDK4 enhancing tumor metastasis behavior

“…PDX model has become an effective tool to evaluate anti-tumor drugs and conduct research on personalized cancer treatment. 25,26 In this study, we established two bladder cancer PDX models, one of which has multi-organ metastasis potential. H&E staining and IHC analysis conrmed that the xenogra tumor well retained the pathological features of the primary tumor.…”