Overcoming drug-resistant cancer mutations with novel inhibitors

A team led by researchers from Oxford Chemistry have recently published a study in Nature Communications investigating the mechanism behind a resistance to the drug ivosidenib that has developed in some types of cancer.

Ivosidenib is an anti-cancer drug approved for treating acute myeloid leukaemia (AML), a cancer of the blood and bone marrow. Ivosidenib targets a mutated enzyme (called isocitrate dehydrogenase 1, IDH1) involved in cancer development and progression.

Mutated IDH1 contributes to the disease development of AML by producing 2-hydroxyglutarate (2-HG). The IDH1 inhibitor ivosidenib binds to the mutated enzyme and suppresses 2-HG production by a process known as allosteric control, whereby a molecule affects the function of a protein by binding to it away from the active site. This suppression of 2-HG production induces clinical responses in relapsed and refractory IDH1-mutant AML. Unfortunately, some patients with AML have become resistant to ivosidenib because of an acquired second genetic mutation in IDH1.

The Oxford team’s investigation focused on the resistance mechanism of this second mutation. The results of their research, including crystallographic and NMR studies, shed light on the mechanism of resistance to ivosidenib at the IDH1 dimer interface. Notably, their work, including experiments in glioma cell lines, demonstrates that it may be possible to overcome this resistance using alternative inhibitors currently in phase 2 clinical trials. Their study also indicates the mechanism of interaction for these alternative inhibitors.

Dr Raphael Reinbold, first author of the study, comments:

Ivosidenib is an important example of a new era of targeted cancer therapeutics with low side effects. Understanding resistance against it and identifying drugs that retain their activity is crucial for the immediate clinical need but also the development of the next generation of these therapeutics.

The work may also be relevant to treating metastatic cholangiocarcinoma (bile duct cancer), which harbours IDH mutations, as well as gliomas and glioblastomas, types of brain cancers that often have poor prognoses. This is because around 80% of low-grade gliomas and secondary glioblastomas also have IDH1 mutations.

Dr Martine Abboud, co-corresponding author of the paper alongside Prof. Chris Schofield, said:

This work exemplifies how allosteric interactions impact active site activity – an example of fundamental molecular research that goes beyond the bench as it has the potential to inform medical practice and co-therapy with real-world implications.

Prof. Schofield added:

Targeting cancer metabolism by small molecules is a field of considerable therapeutic promise – we hope our mechanistic work will help enable new medicines.

Read more about the study in Nature Communications, or view the graphical abstract.