Current understanding of drug resistance mechanisms and therapeutic targets in HER2 overexpressing breast cancers

Abstract

A subset of breast cancers is marked by overexpression of HER2 receptor and activated HER2-mediated signaling. Targeting HER2 offers a unique therapeutic approach for the treatment of such breast cancers. Trastuzumab, lapatinib, and, more recently, pertuzumab, have been approved by FDA to treat HER2 overexpressing breast cancers. Although the drugs effectively target HER2 leading to a favorable clinical response in patients initially, a majority of patients turn refractory to HER2 targeted drugs as early as within a year of administration. Trastuzumab, being the first HER2 targeted drug, has been investigated in detail in relation to acquired resistance, and emerging reports are evident for such drug resistance in lapatinib treated HER2 overexpressing breast cancers as well. This chapter takes a look at the progress of treatment options in HER2 overexpressing breast cancers with focus on mechanisms that are believed to be responsible for drug resistance. We also discuss the current strategies being investigated to overcome drug resistance.