Resistance to Targeted Therapies As a Result of Mutation(s) in the Target

Tyrosine kinase inhibitors (TKIs) are effective clinical therapies in a subset of malignancies defined by oncogenic alterations. Compelling clinical examples include EGFR mutant non-small cell lung cancer and chronic myeloid leukemia. Unfortunately, the effectiveness of these treatments is ultimately limited due to the development of drug resistance most commonly mediated by secondary mutations. These resistance mutations often occur at the gatekeeper residue, like the T315I mutation in BCR-ABL or the T790M mutation in EGFR, but it can also occur outside the gatekeeper residue. In this chapter, we will address the different types of resistance mutations and the mechanisms by which they confer resistance to TKI. We will also discuss the therapeutic strategies developed to overcome these resistance mutations.