Ligand-Independent HER2/HER3/PI3K Complex Is Disrupted by Trastuzumab and Is Effectively Inhibited by the PI3K Inhibitor GDC-0941

Abstract

We described experiments using the MDA-MB-361.1 cell line, which was thought to be an in vivo passaged subclone of the MDA-MB-361 cell line. The MDA-MB-361 cell line harbors HER2 amplification and an activating PIK3CA mutation (E545K). Subsequent molecular profiling of the MDA-MB-361.1 cell line revealed that it is actually a derivative of the MCF7 cell line that was stably transfected to overexpress HER2 (termed MCF7-neo/HER2). MCF7 cells also harbor the activating PIK3CA mutation (E545K). Although the conclusions from the study are unaffected, we apologize for the discrepancy.

Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer

“…The 4 h treatment with T-DM1 or trastuzumab did not result in significant caspase activity (not shown) confirming that the detected cell death is not due to apoptotic activity of the DM1, but caused by the lytic activity of immune cells. Inhibition of HER3 phosphorylation by trastuzumab and the resulting inhibition of the PI3K pathway have been shown to be immediate and critical for the cytostatic effect of trastuzumab [11,29]. To investigate the effect of T-DM1 on AKT phosphorylation, BT-474-M1 cells were treated for 2 h with a dilution series of the antibodies.…”

“…Trastuzumab is known to disrupt ligand-independent HER2/HER3 interactions in HER2-amplified cells [11]. This dissociation leads to the uncoupling of PI3K-AKT signaling and correlates with the antiproliferative effects of trastuzumab.…”

Population pharmacokinetic and covariate analysis of pertuzumab, a HER2-targeted monoclonal antibody, and evaluation of a fixed, non-weight-based dose in patients with a variety of solid tumors

“…The proposed mechanism of action of pertuzumab is distinct from that of trastuzumab, another anti-HER2 mAb. Preclinical studies have shown that trastuzumab binds to a different HER2 epitope (subdomain IV), preventing cleavage of the HER2 extracellular domain (ECD), effectively blocking constitutive activation of truncated receptors, and disrupting ligand-independent complex formation of phosphatidylinositol-3-kinase (PI3K)-HER2-HER3-PI3K [2][3][4][5]. Pertuzumab and trastuzumab have complementary modes of action and the two antibodies bind to their respective epitopes without steric hindrance or competition for binding sites.…”

“…Pertuzumab is a recombinant humanized monoclonal antibody (mAb) against human epidermal growth factor receptor 2 (HER2) with a novel mechanism of action targeting dimerization of the HER2 receptor with other HER-family members (HER1, HER3, and HER4) by binding to the dimerization domain (subdomain II) of the HER2 receptor [1,2]. As a result, in preclinical studies, pertuzumab has…”

“…The potential impact of patient and laboratory characteristics and HER2 target-related variables on pertuzumab PK were investigated in a covariate analysis. The final model was used to confirm selection of fixed, non-weight-based 1 3 been shown to inhibit ligand-activated downstream signaling, leading to reduced tumor cell proliferation and survival [1,2]. The proposed mechanism of action of pertuzumab is distinct from that of trastuzumab, another anti-HER2 mAb.…”