Dual HER2 Targeting Impedes Growth of HER2 Gene–Amplified Uterine Serous Carcinoma Xenografts

Abstract

Purpose Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that commonly harbors HER2 gene amplification. We investigated the effectiveness of HER2 inhibition using lapatinib and trastuzumab in vitro and in xenografts derived from USC cell lines and USC patient derived xenografts (PDXs). Experimental Design Immunohistochemistry and fluorescence in situ hybridization were performed to assess HER2 expression in 42 primary USC specimens. ARK1, ARK2 and SPEC2 cell lines were treated with trastuzumab or lapatinib. Cohorts of mice harboring xenografts derived from ARK2 and SPEC2 cell lines and EnCa1 and EnCa2 primary human USC samples were treated with either vehicle, trastuzumab, lapatinib or the combination of trastuzumab and lapatinib. Acute and chronic post treatment tumor samples were assessed for downstream signaling alterations and examined for apoptosis and proliferation. Results HER2 gene amplification (24%) correlated significantly with HER2 protein over-expression (55%). All models were impervious to single agent trastuzumab treatment. Lapatinib decreased in vitro proliferation of all cell lines and in vivo growth of HER2 amplified xenografts (ARK2, EnCa1). In addition, dual therapy with trastuzumab and lapatinib resulted in significant anti-tumor activity only in ARK2 and EnCa1 tumors. Dual HER2 therapy induced on target alteration of downstream MAPK and PI3K pathway mediators only in HER2 amplified models, and was associated with increased apoptosis and decreased proliferation. Conclusions While trastuzumab alone did not impact USC growth, dual anti-HER2 therapy with lapatinib led to improved inhibition of tumor growth in HER2 amplified USC and may be a promising avenue for future investigation.

Targeted Therapy in the Treatment of Uterine Serous Carcinoma

“…Similarly a study recently published in Clinical Cancer Research suggests that dual targeting of HER2/neu with Trastuzumab and lapatinib led to better inhibition of tumor growth in HER2/neuamplified USC xenografts [20]. These data suggest that there may be improvement in responses if a dual targeting strategy is implemented in the treatment of uterine serous carcinoma.…”

HER2 over-expressing high grade endometrial cancer expresses high levels of p95HER2 variant

“…This concept has gained traction in the BrCa literature leading some investigators to hypothesize dual anti-HER2 therapies could replace cytotoxics chemotherapy for a significant subset of patients [38, 39]. Currently, this concept is untested in EnCa, but pre-clinical models utilizing USC non-immortalized cell lines and patient derived xenografts supported an approach of combining trastuzumab with lapatinib[40]. …”

HER2 over-expressing high grade endometrial cancer expresses high levels of p95HER2 variant

“…This concept has gained traction in the BrCa literature leading some investigators to hypothesize dual anti-HER2 therapies could replace cytotoxics chemotherapy for a significant subset of patients [38,39]. Currently, this concept is untested in EnCa, but pre-clinical models utilizing USC nonimmortalized cell lines and patient derived xenografts supported an approach of combining trastuzumab with lapatinib [40].…”