Secondary IDH1 resistance mutations and oncogenic IDH2 mutations cause acquired resistance to ivosidenib in cholangiocarcinoma

The mutant IDH1 inhibitor ivosidenib improves outcomes for patients with IDH1- mutated cholangiocarcinoma, but resistance inevitably develops. Mechanisms of resistance and strategies to overcome resistance are poorly understood. Here we describe two patients with IDH1 R132C -mutated metastatic chola...

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Published in:NPJ precision oncology 2022-09, Vol.6 (1), p.61-61, Article 61
Main Authors: Cleary, James M., Rouaisnel, Betty, Daina, Antoine, Raghavan, Srivatsan, Roller, Lauren A., Huffman, Brandon M., Singh, Harshabad, Wen, Patrick Y., Bardeesy, Nabeel, Zoete, Vincent, Wolpin, Brian M., Losman, Julie-Aurore
Format: Article
Language:English
Subjects:
631/67/1059/2326
631/67/1504/1329/1326
Cancer Research
Chemotherapy
Cholangiocarcinoma
Drug resistance
Gene Therapy
Human Genetics
Inhibitor drugs
Internal Medicine
Medicine
Medicine & Public Health
Mutation
Oncology
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Summary:The mutant IDH1 inhibitor ivosidenib improves outcomes for patients with IDH1- mutated cholangiocarcinoma, but resistance inevitably develops. Mechanisms of resistance and strategies to overcome resistance are poorly understood. Here we describe two patients with IDH1 R132C -mutated metastatic cholangiocarcinoma who developed acquired resistance to ivosidenib. After disease progression, one patient developed an oncogenic IDH2 mutation, and the second patient acquired a secondary IDH1 D279N mutation. To characterize the putative IDH1 resistance mutation, cells expressing the double-mutant were generated. In vitro, IDH1 R132H/D279N produces (R) -2HG less efficiently than IDH1 R132H. However, its binding to ivosidenib is impaired and it retains the ability to produce (R) -2HG and promote cellular transformation in the presence of ivosidenib. The irreversible mutant IDH1 inhibitor LY3410738 binds and blocks (R) -2HG production and cellular transformation by IDH1 R132H/D279N. These resistance mechanisms suggest that IDH1 -mutated cholangiocarcinomas remain dependent on (R) -2HG even after prolonged ivosidenib treatment. Sequential mutant IDH inhibitor therapy should be explored as a strategy to overcome acquired resistance to mutant IDH inhibitors.
ISSN:2397-768X
2397-768X
DOI:10.1038/s41698-022-00304-5