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.
Highlights
High grade serous ovarian cancer (HGS-OC) is one of the deadliest cancers, with detection most commonly occurring at late stages when it has already spread to the peritoneum
Receptor tyrosine-protein kinase human epidermal growth factor receptor 2 (HER2) belongs to an avian erythroblastosis oncogene B (ERBB) signaling pathway which includes structurally related receptor kinases epidermal growth factor receptor (EGFR) (HER1), HER3 and HER4 and their ligands (Hynes and Lane, 2005)
HER2 is a receptor with no known natural ligand that upon dimerization with EGFR, HER3 or HER4 activates RAS/extracellular receptor kinase (ERK) and PI3K/AKT signaling pathways (Arteaga and Engelman, 2014; Yakes et al, 2002) and promotes cell growth, cell migration and invasion (Appert-Collin et al, 2015; Hynes and Lane, 2005)
Summary
High grade serous ovarian cancer (HGS-OC) is one of the deadliest cancers, with detection most commonly occurring at late stages when it has already spread to the peritoneum. Recent efforts in oncology have focused on testing targeted therapies chosen based on a molecular characterization of individual tumors. Among these are inhibitors of HER receptors, primarily EGFR and HER2. Receptor tyrosine-protein kinase HER2 belongs to an ERBB signaling pathway which includes structurally related receptor kinases EGFR (HER1), HER3 and HER4 and their ligands (Hynes and Lane, 2005). HER2 is a receptor with no known natural ligand that upon dimerization with EGFR, HER3 or HER4 activates RAS/ERK and PI3K/AKT signaling pathways (Arteaga and Engelman, 2014; Yakes et al, 2002) and promotes cell growth, cell migration and invasion (Appert-Collin et al, 2015; Hynes and Lane, 2005). Increased levels of HER2 have been shown to affect rates of degradation for HER2-containing heterodimers, prolonging the pathway stimulation (Huang et al, 1999; Parakh et al, 2017; Sak et al, 2013)
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