Synthetic sickness with molecularly targeted agents against the egfr pathway

The discovery of novel synthetic sick and synthetic lethal interactions in tumors is paramount in the era of personalized medicine. Through these mechanisms, tumor cells may be preferentially killed while sparing healthy bystander tissue, thereby minimizing side effects. In this chapter, we will discuss in detail the nuances of synthetic sickness. Additionally, we will focus on one such potential induced synthetic sickness strategy involving the combined inhibition of the EGFR and PARP pathways. This concept revolves around the recent appreciation of several proteins within the EGFR pathway and their roles in DNA damage repair. We will discuss the mechanisms by which inhibition of the EGFR pathway induces a DNA repair deficiency, which is subsequently exploited by PARP inhibition. Clinical testing of these strategies is currently underway, and if successful, may impact the therapy of multiple tumor types.