[Lani]

Introduction

The mechanism by which trastuzumab exerts its antitumor activity is not fully understood. Trastuzumab has been suggested to induce antibody-dependent cellular cytotoxicity (ADCC) (Clynes et al., 2000), inhibit HER2 extracellular domain cleavage (Molina et al., 2001), or inhibit PI3K/AKT survival signaling, either by downregulating HER2 signaling (Yakes et al., 2002) or by increasing PTEN membrane localization and phosphatase activity, leading to a decline in PI3K/AKT pathway activation and inhibition of proliferation (Nagata et al., 2004). In addition, activation of HER-related receptors, such as HER3, or non-HER receptors, such as insulin-like growth factor I receptor, have been suggested in preclinical studies to increase PI3K/AKT signaling thereby limiting trastuzumab efficacy ([Lu et al., 2001] and [Sergina et al., 2007]). In spite of this, it is still largely unclear why almost half of the breast cancer patients that overexpress HER2 are initially nonresponsive to trastuzumab-based therapy even when combined with chemotherapy or eventually become resistant to trastuzumab during treatment ([Cobleigh et al., 1999], [Slamon et al., 2001] and [Vogel et al., 2002]). An understanding of the resistance mechanisms would stimulate the development of rational drug combinations to circumvent resistance and allow better selection of patients likely to respond.