ISAL 2025 | Mechanisms of resistance to menin inhibitors in AML and strategies to overcome resistance

Resistance occurring to a highly specific, highly potent, single molecule targeted therapy is not a surprise and of course wasn’t a surprise for us. We started relatively early on during the preclinical development to explore this question, which mechanisms can lead to menin inhibitor resistance. Even before the menin inhibitors actually entered into the clinic, we had predicted a set of point mutations that would impair binding of revumenib to the pocket within menin. And we were pretty sure that this could be something that’s relevant in the clinic. And indeed, in these first Phase I and II patient cohorts under revumenib treatment, these point mutations within menin were found and the principle of that is very similar to what we know from kinase inhibitors. So it’s basically target-site mutations that interfere with drug binding and therefore reduce the sensitivity of those cells. We know by now that this phenomenon is there are some of these mutations that seem to have a class effect towards the different menin inhibitors. The degree to which they impair binding of the respective drugs is different though. So that is going to be something where the chemical properties of the different menin inhibitors are going to be of interest and where we will probably see significant differences regarding the spectrum and type and likelihood of mutations to occur between the different menin inhibitors. Aside from that, a mechanism that is much more diverse and much less clearly explored yet is non-genetic resistance to menin inhibitors. Apparently, cells under constant treatment with menin inhibitors are able to adapt to the treatment. And while the drug still binds to its target and it still works on the molecular level, these cells sort of learn to work around that. And so these are the two big aspects of the genetic and the non-genetic resistance to menin inhibitors is something that we will have to keep in mind when we treat these patients. An aspect that’s going to be very important in the future is to apply combination therapy regimens. And clinical trials have started to do that. Menin inhibitors in combination with standard chemotherapy in combination with venetoclax and azacitidine and also in combination with FLT3 inhibitors and I think these strategies will really help to diversify the selective pressure that we put on these leukemias and reduce the likelihood that we will have escape mutations as we see it now relatively frequently in these clinical trials that use the menin inhibitors as a monotherapy.

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