Mechanisms of Resistance to HER2

Several targeted agents interfering with signaling effectors have been evaluated and have demonstrated efficacy in breast cancer. Understanding the molecular mechanisms underlying their success or failure is critical and, to this aim, the neoadjuvant setting offers unique opportunities for testing agents, sampling tumors, and exploring novel study design, such as the window-of-opportunity trials. The resistance observed in this setting is generally primary, although some alterations, such as alternative growth factors pro-duction and angiogenic factors expression, gained during tumor progression before diagnosis and beginning of treatment, are involved also in secondary/acquired resistance. The large body of information gained on the HER/ErbB family of tyrosine kinase receptors, (RTKs) functioning and the success of anti-HER2 drugs (1) explain why the majority of studies on resis-tance to targeted drugs is focused on anti-HER2 drugs. Notably, several signaling proteins responsible for resistance to anti-HER2 drugs, including, for instance, Akt activation, PTEN deletion, acti-vation of growth factors receptors not belonging to HER family etc., are often involved in the resistance against other targeted agents