Understanding the Mechanism and Sensitivity of BCL-2 Inhibitors

John Seymour, MBBS, FRACP, PhD, director of hematology at the Peter MacCallum Cancer Center and the Royal Melbourne Hospital in Melbourne, Australia, explains the mechanism of action of BCL-2 inhibitors.

BCL-2 inhibitors, such as venetoclax (Venclexta) work by targeting the BCL-2 protein, which plays a key role in preventing apoptosis, or programmed cell death. According to John Seymour, MD, overexpression of BCL-2 allows cancer cells to evade apoptosis, leading to uncontrolled growth.

Venetoclax specifically binds to BCL-2, displacing apoptotic activators, which then reinitiate the apoptosis process. Sensitivity to venetoclax depends not only on BCL-2 levels but also on the presence and displacement of apoptotic activators and other factors like MCL-1 that might interfere. Seymour highlights that the drug's potent and rapid induction of apoptosis necessitates a gradual dose ramp-up to manage cytoreduction and mitigate risks of patient morbidity.

Transcription:

0:10 | BCL-2 inhibitors work by binding to and preventing the action of BCL-2. In the normal cell death pathway, as cells age, they should die by apoptosis. Overexpression of BCL-2 prevents activation of that pathway. Delivering a BCL-2 inhibitor [like] venetoclax binds to BCL-2 and then displaces those apoptotic activators, such as BIM and BID that then bind to and activate that pathway.

0:52 | Understanding that it is not solely what level of BCL-2 is present that determines sensitivity, but what are the apoptotic activators that are bound to BCL-2? How will they be displaced? Are there other factors present, such as MCL-1, that can potentially quench those factors, or will they go on to trigger apoptosis? So, it is understanding the dynamic balance between those regulators that determines the sensitivity to venetoclax. But the potency and the rapidity of induction of apoptosis is what leads to the need for that gradual dose ramp-up and cytoreduction and avoid those biochemical issues that can lead to significant patient morbidity.