Apoptosis in targeted therapy responses: the role of BIM

The treatment of advanced cancer has undergone a dramatic change over the past 5 years. Laboratory findings have led to the development of newer treatments, often termed "targeted therapies," which are significantly different from traditional chemotherapies in that they aim to disrupt critical processes needed specifically for a cancer cell's growth and survival, therefore, eliminating some of the general toxicities of chemotherapies. Cancers with specific genetic abnormalities, for instance epidermal growth factor receptor (EGFR) mutant lung cancers and HER2 amplified breast cancers, are often sensitive to these new targeted therapies that can specifically inhibit the function of EGFR or HER2. This has led to more routine prospective genetic testing of cancers to determine which patients should get these treatments instead of chemotherapy. However, emerging clinical data have revealed that some cancers with these genetic mutations (that predict a response) are unexpectedly not sensitive to these treatments. There is a growing body of evidence suggesting a deficiency in apoptosis following targeted therapy treatment can lead to this lack of sensitivity. Moreover, the pro-apoptotic protein BIM has emerged as a key modulator of apoptosis following effective targeted therapy, and deficiencies in BIM expression result in targeted therapy resistance. In this chapter, we summarize what is known about the role of BIM in targeted therapy-induced apoptosis, and discuss the implications of deficient BIM in cancers treated with these therapies. We highlight potential pharmaceutical strategies to overcome low BIM expression and sensitize these cancers to targeted therapies.