Abstract
BackgroundElevated expression of erbB3 receptor has been reported to induce resistance to therapeutic agents, including trastuzumab in erbB2-overexpressing breast cancer. Our recent studies indicate that erbB3 interacts with both erbB2 and IGF-1 receptor to form a heterotrimeric complex in trastuzumab-resistant breast cancer cells. Herein, we investigate the antitumor activity of MM-121/SAR256212, a fully human anti-erbB3 antibody (Ab), against two erbB2-overexpressing breast cancer cell lines resistant to trastuzumab.MethodsMTS-based proliferation assays were used to determine cell viability upon treatment of trastuzumab and/or MM-121/SAR256212. Cell cycle progression was examined by flow cytometric analysis. Western blot analyses were performed to determine the expression and activation of proteins. Tumor xenografts were established by inoculation of the trastuzumab-resistant BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with trastuzumab and/or MM-121/SAR256212 via i.p injection to determine the Abs’ antitumor activity. Immunohistochemical analyses were carried out to study the Abs’ inhibitory effects on tumor cell proliferation and induction of apoptosis in vivo.ResultsMM-121 significantly enhanced trastuzumab-induced growth inhibition in two sensitive and two resistant breast cancer cell lines. MM-121 in combination with trastuzumab resulted in a dramatic reduction of phosphorylated erbB3 (P-erbB3) and Akt (P-Akt) in the in vitro studies. MM-121 combined with trastuzumab did not induce apoptosis in the trastuzumab-resistant cell lines under our cell culture condition, rather induced cell cycle G1 arrest mainly associated with the upregulation of p27kip1. Interestingly, in the tumor xenograft model established from the trastuzumab-resistant cells, MM-121 in combination with trastuzumab as compared to either agent alone dramatically inhibited tumor growth correlated with a significant reduction of Ki67 staining and increase of cleaved caspase-3 in the tumor tissues.ConclusionsThe combination of MM-121 and trastuzumab not only inhibits erbB2-overexpressing breast cancer cell proliferation, but also promotes the otherwise trastuzumab-resistant cells undergoing apoptosis in an in vivo xenografts model. Thus, MM-121 exhibits potent antitumor activity when combined with trastuzumab under the studied conditions. Our data suggest that further studies regarding the suitability of MM-121 for treatment of breast cancer patients whose tumors overexpress erbB2 and become resistant to trastuzumab may be warranted.
Highlights
Elevated expression of erbB3 receptor has been reported to induce resistance to therapeutic agents, including trastuzumab in erbB2-overexpressing breast cancer
MM-121 significantly enhances the inhibitory effects of trastuzumab on erbB2+ breast cancer cell lines associated with the inactivation of erbB3/Phosphoinositide 3-kinase (PI-3K)/Akt signaling To explore whether the anti-erbB3 Ab MM-121 may enhance the activity of trastuzumab against erbB2+ breast cancers, we investigated the combinatorial effects of MM121 and trastuzumab on erbB3 signaling and cell proliferation in two erbB2+ breast cancer cell lines (SKBR3 and BT474)
We found that treatment with trastuzumab mainly reduced the levels of phosphorylated erbB3 (P-erbB3) and phosphorylated Akt (P-Akt) in both SKBR3 and BT474 cell lines, whereas MM-121 had no obvious effects on P-erbB3 and P-Akt
Summary
Elevated expression of erbB3 receptor has been reported to induce resistance to therapeutic agents, including trastuzumab in erbB2-overexpressing breast cancer. We investigate the antitumor activity of MM-121/SAR256212, a fully human anti-erbB3 antibody (Ab), against two erbB2-overexpressing breast cancer cell lines resistant to trastuzumab. For the erbB3 receptor, because of its lack of or low kinase activity [16,17], targeting of erbB3 with a monoclonal Ab is the only strategy currently under preclinical investigation [18,19] and clinical studies in patients with advanced solid tumors (http://www.clinicaltrials.gov). MM121/SAR256212 is a fully human anti-erbB3 monoclonal IgG2 Ab being co-developed by Merrimack Pharmaceuticals and Sanofi It inhibits ligand-induced dimerization of erbB3 and erbB2 and subsequently inactivates the downstream signaling. Whether MM-121 holds potential to overcome trastuzumab resistance and enhance trastuzumab-mediated growth inhibition in erbB2+ breast cancer cells remains unclear
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