A matter of life or death

Summary

Resistance to apoptosis enables malignant cells to survive in the presence of otherwise lethal chromosomal, cellular and metabolic alterations. As a consequence, dependence on pro-survival proteins is a potentially targetable weakness of these cancer cells. The research described in this thesis focuses on pro-survival BCL-2 family protein MCL-1 as therapeutic target in multiple myeloma (MM).

In MM, a malignancy of plasma cells that reside in the bone marrow, MCL-1 is often overexpressed, resulting in apoptosis resistance. MCL-1 and can be pharmacologically inhibited using small-molecule inhibitors, some of which are currently being tested in early-stage clinical trials. We studied MCL-1 inhibitor sensitivity of a large panel of patient-derived MM cells and MM cell lines, and found that a large fraction of MM depends on MCL-1 for survival. Moreover, amplification of 1q21 may be a diagnostic marker to predict MCL-1 inhibitor sensitivity in MM patients, since MCL-1 inhibitor sensitivity is particularly high in this patient subset. In addition to MCL-1, we show that BCL-2 family proteins BCL-2 and BCL-XL contribute to apoptosis resistance in MM. As a result, combining MCL-1 inhibition with BCL-2 or BCL-XL inhibition led to synergistic apoptosis induction.

Since MCL-1 is expressed in many healthy tissues, it is important to study molecular regulation of MCL-1 in MM, because this may provide novel strategies to indirectly inhibit MCL-1 in a cancer- or tissue-dependent manner. By studying molecular regulation of MCL-1, we found that besides by upregulation at the transcriptional level, high MCL-1 expression in MM can result from protein stabilization at the post-translational level.

In conclusion, MCL-1 inhibition is a promising therapeutic strategy in MM. Further studying the complex regulation of MCL-1 will aid in finding new rational drug combinations that can exploit MCL-1 dependence and induce apoptosis in MM, and potentially in other cancer types.