論文 - 詳細
| RRC ID | 89785 |
|---|---|
| 著者 | Wan J, Saatcioglu HD, Ellis H, Aguado-Fraile E, Xu Q, Kondo H, Manguso RT, Gritti I, Norden BL, Noble C, Corcoran RB, Lubner SJ, Javle M, Abou-Alfa GK, Cleary JM, Kelley RK, Borad MJ, Macarulla T, Oh DY, Daigle S, Gliser C, Pandya S, Choe S, Tron AE, Bardeesy N. |
| タイトル | MAPK Pathway Mutations Emerge in Mutant IDH1 Inhibitor-Resistant Cholangiocarcinoma and Attenuate the IFN Response. |
| ジャーナル | Clin Cancer Res |
| Abstract |
PURPOSE:Mutant IDH1 (mIDH1) defines a therapeutically targetable subtype of intrahepatic cholangiocarcinoma (ICC), with the mIDH1 inhibitor ivosidenib approved for advanced disease. A subset of patients experiences prolonged disease stabilization; however, the molecular basis for eventual progression remains poorly defined. EXPERIMENTAL DESIGN:We performed molecular profiling of matched baseline and postprogression circulating tumor DNA (ctDNA) samples from patients with mIDH1 ICC enrolled in the ClarIDHy phase III trial. Functional studies were conducted to characterize candidate resistance mechanisms. RESULTS:Longitudinal ctDNA analysis of 18 patients treated with ivosidenib for >6 months revealed emergent genomic alterations in multiple cases. Acquired mutations in mitogen-activated protein kinase (MAPK) pathway genes (KRAS, NRAS, MAP2K1, NF1) were identified in five cases, with instances of concurrent alterations and/or high variant allele fractions (VAF). Additional candidate resistance events included a secondary IDH1 mutation and a hotspot IDH2 mutation, detected at low VAF in the same patient. Functional studies showed that these IDH mutations conferred sustained 2-hydroxyglutarate production and ivosidenib resistance, whereas MAPK activation blunted gene expression induced by ivosidenib plus IFNγ, a key therapeutic output of mIDH1 inhibition. In parallel, baseline ctDNA profiling of 81 patients revealed that ARID1A mutations and elevated mIDH1 VAF were associated with reduced clinical benefit. CONCLUSIONS:MAPK pathway alterations represent a recurrent mechanism of resistance to mIDH1 inhibition in ICC, whereas emergent IDH1/IDH2 mutations appear infrequent. Functional data suggest that MAPK-mediated resistance may involve impaired IFN signaling. These results support MAPK-directed combination strategies and highlight the utility of ctDNA profiling to identify predictive and resistance biomarkers in mIDH1-driven ICC. |
| 巻・号 | 32(5) |
| ページ | 925-937 |
| 公開日 | 2026-3-2 |
| DOI | 10.1158/1078-0432.CCR-25-3284 |
| PII | 771243 |
| PMID | 41460204 |
| PMC | PMC13056288 |
| MeSH | Aged Bile Duct Neoplasms* / drug therapy Bile Duct Neoplasms* / genetics Bile Duct Neoplasms* / pathology Cholangiocarcinoma* / drug therapy Cholangiocarcinoma* / genetics Cholangiocarcinoma* / metabolism Cholangiocarcinoma* / pathology Circulating Tumor DNA / blood Circulating Tumor DNA / genetics Drug Resistance, Neoplasm* / genetics Female Glycine / analogs & derivatives Humans Interferons* / pharmacology Isocitrate Dehydrogenase* / antagonists & inhibitors Isocitrate Dehydrogenase* / genetics MAP Kinase Signaling System* / drug effects MAP Kinase Signaling System* / genetics Male Middle Aged Mutation* Pyridines / administration & dosage Pyridines / therapeutic use |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 11 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 4.8 |
| リソース情報 | |
| ヒト・動物細胞 | RBE(RCB1292) |