BCL2 inhibition with venetoclax has recently become a standard-of-care treatment for patients with chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). It is also being trialled in other types of blood cancer as well as in solid cancers, such as breast and lung.
Venetoclax is a small molecule inhibitor which selectively targets the pro-survival protein BCL2. In tumor cells that are heavily reliant on BCL2, venetoclax treatment acts to drive their apoptotic cell death which is mediated by BAX and BAK. These mediators represent the point-of-no-return for apoptosis induction.
This unique mechanism of venetoclax’s action is distinct from conventional cytotoxic agents, which indirectly cause cell death by inducing DNA damage or mitotic arrest. Proliferative cells are therefore more susceptible to these agents, but this results in non-proliferative tumour cells to persist and contribute to chemoresistance. Therefore, understanding whether cell cycle status of a tumour cell affects drug sensitivity could provide insight to how we can prevent drug resistance from emerging.
However, whether the cell cycle status affects venetoclax sensitivity is unknown. An intriguing observation in CLL patients treated with venetoclax suggests that tumor cell proliferation might impact venetoclax sensitivity. While venetoclax treatment rapidly clears the leukemic cells from the peripheral blood in CLL patients, the tumor burden in the lymph nodes is usually resolved less quickly. The prevailing notion is that survival signals from the lymph node microenvironment blunt the sensitivity of resident leukemic cells to venetoclax. It is also known that the leukemic cells in the lymph nodes are proliferating whereas the highly sensitive leukemic cells in the peripheral blood are non-proliferating. Thus, we hypothesize that proliferation could affect a tumour cell’s sensitivity to venetoclax.
To test this idea, we assessed whether the proliferation of primary leukemic cells ex vivo or of blood cancer cell lines affect venetoclax sensitivity. Given that venetoclax acts through BAX/BAK, we determined if any observed effect is dependent on the specific induction of apoptosis by conducting identical experiments in BAX/BAK-deficient cells.
Importantly, findings from our study could have implications for how we might be able to use venetoclax more effectively in the clinic.