ESH CLL 2022 | Mechanisms of resistance to targeted therapies in CLL
In this video, Sigrid Skånland, PhD, Oslo University Hospital, Oslo, Norway, highlights resistance mechanisms of chronic lymphocytic leukemia (CLL) cells to targeted therapies, including Bruton’s tyrosine kinase (BTK) inhibitors, the BCL-2 inhibitor venetoclax, and PI3 kinase inhibitors. Dr Skånland first explains the most common causes of resistance to BTK inhibitors, including mutations of BTK and mutations in the downstream protein phospholipase C gamma (PLC-gamma). Dr Skånland then explains that an upregulation in the mitogen-activated protein kinase (MAPK) pathway may cause CLL cells to develop resistance to PI3 kinase inhibitors. This interview took place during the 2nd ESH Translational Research Conference on Chronic Lymphocytic Leukemia (ESH CLL), 2022.
Transcript (edited for clarity)
We have three main classes of targeted therapies in CLL: it’s BTK inhibitors, PI3 kinase inhibitors and the BCL-2 antagonist venetoclax, and we are getting more familiar with the resistance mechanisms to these. The most common one for BTK inhibitors is change of the target, so mutations in BTK, and we also see mutations in the downstream protein, PLC gamma. And also, when it comes to venetoclax, one resistance mechanism is mutation in BCL2...
We have three main classes of targeted therapies in CLL: it’s BTK inhibitors, PI3 kinase inhibitors and the BCL-2 antagonist venetoclax, and we are getting more familiar with the resistance mechanisms to these. The most common one for BTK inhibitors is change of the target, so mutations in BTK, and we also see mutations in the downstream protein, PLC gamma. And also, when it comes to venetoclax, one resistance mechanism is mutation in BCL2.
For PI3 kinase inhibitors, it has not been so clear and there haven’t been any descriptions of mutations in PI3 kinase that can explain the mutations and rather it seems to be upregulations of bypass mechanisms. So there are some reports on upregulations of other p110 isoforms and then the target and one recent study from Jennifer Brown’s group also showed that there is upregulation or activation of the MAP kinase pathway that is associated with the resistance to idelalisib.
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