MAPK Pathway Mutations Emerge in Mutant IDH1 Inhibitor–Resistant Cholangiocarcinoma and Attenuate the IFN Response

作者：Jinkai Wan, Hatice D. Saatcioglu, Haley Ellis, Elia Aguado-Fraile, Qin Xu, Hiroshi Kondo, Robert T. Manguso, Ilaria Gritti, Bryanna L. Norden, Carolina Noble, Ryan B. Corcoran, Sam Joseph Lubner, Milind Javle, Ghassan K. Abou‐Alfa, James M. Cleary, Robin Katie Kelley, Mitesh J. Borad, Teresa Macarulla, Do Youn Oh, Scott R. Daigle, Camelia Gliser, Susan Pandya, Sung Choe, Adriana E. Tron, N. Bardeesy · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1078-0432.ccr-25-3284 · 被引用次数：3 · 研究领域：Cholangiocarcinoma and Gallbladder Cancer Studies、Chromatin Remodeling and Cancer、Genomics and Chromatin Dynamics

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 ...