Secondary IDH1 resistance mutations and oncogenic IDH2 mutations cause acquired resistance to ivosidenib in cholangiocarcinoma
© 2022. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:6 |
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| Enthalten in: |
NPJ precision oncology - 6(2022), 1 vom: 02. Sept., Seite 61 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cleary, James M [VerfasserIn] |
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| Anmerkungen: |
Date Revised 30.03.2023 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1038/s41698-022-00304-5 |
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| PPN (Katalog-ID): |
NLM345734025 |
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| 245 | 1 | 0 | |a Secondary IDH1 resistance mutations and oncogenic IDH2 mutations cause acquired resistance to ivosidenib in cholangiocarcinoma |
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| 520 | |a © 2022. The Author(s). | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Daina, Antoine |e verfasserin |4 aut | |
| 700 | 1 | |a Raghavan, Srivatsan |e verfasserin |4 aut | |
| 700 | 1 | |a Roller, Lauren A |e verfasserin |4 aut | |
| 700 | 1 | |a Huffman, Brandon M |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Harshabad |e verfasserin |4 aut | |
| 700 | 1 | |a Wen, Patrick Y |e verfasserin |4 aut | |
| 700 | 1 | |a Bardeesy, Nabeel |e verfasserin |4 aut | |
| 700 | 1 | |a Zoete, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a Wolpin, Brian M |e verfasserin |4 aut | |
| 700 | 1 | |a Losman, Julie-Aurore |e verfasserin |4 aut | |
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