Abstract
Trastuzumab, an anti-ErbB2 humanized antibody, brings benefit to patients with ErbB2-amplified metastatic breast cancers. However, the resistance to trastuzumab is common. Our previously reported H2-18, an anti-ErbB2 antibody, potently induced programmed cell death in trastuzumab-resistant breast cancer cells. Here, we aim to investigate the antitumor efficacy of H2-18 in combination with the pan-PI3K inhibitor GDC-0941 in trastuzumab-resistant breast cancer cell lines. The results showed that H2-18 and GDC-0941 synergistically inhibited the in vitro proliferation of BT-474, SKBR-3, HCC-1954 and HCC-1419 breast cancer cells. H2-18 plus GDC-0941 showed significantly enhanced programmed cell death-inducing activity compared with each drug used alone. The combination of H2-18 and GDC-0941 did not increase the effect of single agent on ROS production, cell cycle and ErbB2 signaling. Importantly, the in vivo antitumor efficacy of H2-18 plus GDC-0941 was superior to that of single agent. Thus, the enhanced in vivo antitumor efficacy of H2-18 plus GDC-0941 may mainly be attributable to its increased programmed cell death-inducing activity. Collectively, H2-18 plus GDC-0941 could effectively inhibit tumor growth, suggesting the potential to be translated into clinic as an efficient strategy for ErbB2-overexpressing breast cancers.
Highlights
Breast cancer has been the most commonly diagnosed cancer and the principle cause of cancer-related mortality in women worldwide [1]
We evaluated the ability of GDC-0941 to inhibit the growth of BT-474, SKBR-3, HCC-1954 and HCC-1419 breast cancer cell lines
As ROS was involved in programmed cell death induced by H2-18, we explored whether the addition of GDC-0941 to H2-18 would affect ROS production
Summary
Breast cancer has been the most commonly diagnosed cancer and the principle cause of cancer-related mortality in women worldwide [1]. According to breast cancer treatment (PDQ®), standard treatments of breast cancer can be divided to 5 types: surgery, radiation therapy, chemotherapy, hormone therapy, and targeted therapy. ErbB2-targeted therapy is a successful example as personalized cancer treatment that has made a significant progress in clinical outcomes. ErbB2 ( known as HER2) is a member of epidermal growth factor receptor family [2]. Overexpression of ErbB2 is found in about 25%–30% of human breast cancers, and is associated with tumorigenesis, cancer progression and poor prognosis [3, 4]. ErbB2 activation is dependent on ErbB2 homodimers or heterodimers with other ErbB family members (ErbB1, 3, 4), which could stimulate constitutive phosphorylation of ErbB2 and initiate the main downstream PI3K/AKT pathway and MAPK pathway, culminating in tumor growth
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