Abstract

Despite an increasing array of new cancer therapies, drug resistance is an almost universal phenomenon that can be traced to the presence of rare subclonal populations that act as a reservoir for the emergence of drug resistance. The emergence of drug resistance ultimately proves fatal for the majority of patients, and therefore the early detection of resistance and the identification of novel strategies to overcome the underlying mechanisms is a subject of intense activity world-wide.

For these reasons, there is renewed interest in the use of screens capable of deliberately engineering into the cancer genome random mutational events that can then be tested for their ability to cause drug resistance in an unbiased fashion. Such screens, if sufficiently unbiased, could in theory capture the entire breadth of genetic resistance effectors for any drug. Recent studies have demonstrated the power of both genome-wide gain-of-function (GoF) and loss-of-function (LoF) screens using CRISPR and lentiviral shRNA technologies to identify clinically relevant drug resistance mechanisms in cancer. Here we will discuss the potential role for these in systematically defining the complete repertoire of genetic mechanisms of resistance for cancer drugs.