The role of autophagy in HER2-targeted therapy

Abstract

Macroautophagy (hereafter referred to as autophagy) is a highly conserved, intracellular degradation process characterised by de novo formation of autophagosomes. These double membraned organelles engulf and deliver cargo, for example damaged organelles and protein aggregates, to lysosomes for degradation and recycling. Autophagy is primarily a stress response mechanism activated to survive unfavourable conditions such as starvation or hypoxia. In addition, autophagy functions in differentiation, immune responses against invading microorganisms and tissue remodelling in mammalian cells. Besides its cytoprotective nature, and depending on the context, autophagy can as well support cell death. Based on autophagy’s cytoprotective, cytotoxic and developmental influences, it does not come as a surprise that this mechanism is involved in tumourigenesis, tumour development and the response to anticancer therapies. HER2 is a receptor tyrosine kinase that activates downstream signalling pathways involved in cellular survival, growth and proliferation. Amplification of the gene and subsequent overexpression of the HER2 protein lead to increased activation of downstream signalling and are implicated in several cancer types. HER2-targeted therapies are valuable treatment options for HER2 amplified cancers. However, pre-existing and acquired resistance remain a clinical challenge. Autophagy has been discussed in several scenarios in HER2 amplified cancers. Generally, HER2+ tumours have been shown to exhibit low levels of proteins essential for autophagy. Moreover, a protein involved in autophagy activation, Beclin-1, was shown to interact directly with HER2 at the cellular membrane. The signalling cascade activated by HER2 also activates mTOR, a negative regulator of autophagy. In the context of resistance formation against HER2-targeting treatment, autophagy has often been reported to be upregulated, and resistance has been shown to be abrogated through autophagy inhibition. Since the autophagy inhibitors chloroquine and hydroxychloroquine are approved drugs for the treatment of malaria, autophagy inhibition is discussed as an option to enhance the effect of certain anticancer treatments or to overcome resistance against cancer therapies. In this review we focus on autophagy and its role in the response to HER2-targeted therapies for breast and gastrointestinal tumours.