Researchers Uncover Multiple Paths to Resistance Against a Key Leukemia Drug

Researchers reveal mitochondrial mutations cause drug resistance in leukemia. The new findings could help detect early resistance during cancer treatment.

Researchers from Max Planck Institute of Biophysics and KU Leuven in Belgium have shown in a new study that resistance to venetoclax, an important precision medicine used to treat chronic lymphocytic leukemia, is conveyed through multiple different routes rather than a single mechanism. The findings, published in Advanced Science, provide new insights into why some patients relapse after initially responding well to treatment and how this can be tackled with next-generation medicines.

Text: Nena Testelmans

Chronic lymphocytic leukemia is a type of blood cancer commonly treated with venetoclax, a precision medicine drug. Venetoclax is a targeted therapy that works by inhibiting BCL-2, a protein that helps cancer cells to avoid their natural self-elimination process, known as apoptosis. Although many patients initially respond well to venetoclax treatment, resistance frequently develops over time, so cancers gradually lose their sensitivity to the drug.

Different mutations, different forms of resistance

To better understand how venetoclax resistance emerges, the international team of researchers investigated nine leukemia-associated mutations in BCL-2, the molecular target of venetoclax.

The results revealed that resistance is not caused by a single mechanism. Instead, the BCL-2 mutations interfere with venetoclax action in different ways, thereby preventing cancer cells from undergoing cell death.

“We show that resistance to venetoclax is not a uniform process,” says Geert Bultynck, professor of Molecular and Cellular Medicine at KU Leuven. “Different genetic changes in BCL-2 can help cancer cells evade treatment through distinct mechanisms. Understanding these differences may ultimately help guide more personalized treatment strategies.” 

The researchers also examined how these mutations affect the activity of sonrotoclax, a next-generation treatment currently under development. Sonrotoclax remained capable of targeting BCL-2 regardless of the patient mutations present, although its effectiveness varied depending on the specific mutation and requires further investigation.

Towards more personalized cancer care

The findings provide a framework for understanding how leukemias adapt to BCL-2-targeted therapies. They may help physicians better predict which patients are at risk of developing resistance and guide the development of future drugs that remain effective even when cancers adapt to therapy. In this way, the study brings personalized cancer treatment one step closer.

“Our results show that a single drug is unlikely to be enough to prevent and tackle venetoclax resistance. Future therapies will need to take into account the different ways in which BCL-2 mutations enable cancer cells to escape venetoclax treatment.”

- Ana García-Sáez 

“Our results show that a single drug is unlikely to be enough to prevent and tackle venetoclax resistance,” concludes Ana García-Sáez of the Max Planck Institute of Biophysics. “Future therapies will need to take into account the different ways in which BCL-2 mutations enable cancer cells to escape venetoclax treatment,”.

More information

The study “Cancer-Associated BCL-2 Mutants Reveal Mechanisms Towards Venetoclax Resistance” by Aufdermauer & de Ridder et al. was published in Advanced Science. The research was the result of a close collaboration between the Max Planck Institute of Biophysics, KU Leuven, University of Cologne, and University of Toronto. The project was jointly led by Ana García-Sáez (Max Planck Institute of Biophysics) and Geert Bultynck (KU Leuven).