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

Abstract

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.

RIPK3 deficiency blocks R-2-hydroxyglutarate–induced necroptosis in IDH-mutated AML cells

“…Several clinical studies have shown that HMAs exerted better effects in AML and glioma patients with mIDHs (40)(41)(42). Considering the emergence of resistance to IDH inhibitors (43), restoring RIPK3 expression may be a potential therapeutic strategy in IDH-mutated AML. In the absence of leukemia cell lines naturally carrying mIDHs, our attempts to directly investigate that HMA-induced necroptosis and its influence on RIPK3 expression faced challenges.…”

Targeting AXL Using the AVB-500 Soluble Receptor and through Genetic Knockdown Inhibits Bile Duct Cancer Growth and Metastasis

“…However, the study showed that the high toxicity of cabozantinib limits its use in cholangiocarcinoma patients. In addition, the use of other targeted treatments, including pemigatinib (FGFR2) and ivosidanib (IDH1), is hindered by mutation-mediated drug resistance [ 8 , 9 ]. While there is a strong need to identify more potent and specific therapeutic targets, our data support AVB-500 to control both primary and metastatic bile duct cancers.…”

“…Additionally, another targeted therapy, ivosidanib, targeting isocitrate dehydrogenase-1 (IDH1) mutations, also showed promising results in phase III clinical trials with enhanced progression-free survival [ 7 ]. However, secondary mutations and acquired resistance to FGFR2 and IDH1 targeted therapies, along with the high toxicities observed in a phase II trial with cabozantinib, which targets VEGFR2, MET and AXL, indicate that it is crucial to identify new, specific targeted therapies that possess less normal tissue toxicity to treat bile duct cancer [ 8 , 9 , 10 ].…”

Precision Oncology Targets in Biliary Tract Cancer

“…The initial results were disappointing, with the intention-to-treat analysis demonstrating significantly improved progression-free survival (PFS) in the treatment arm, but no significant difference in overall survival (OS), and an underwhelming ORR of 2.4%, representing three partial responses [ 27 ]. However, the results adjusting for crossover into the treatment arm were able to demonstrate modest improvement in OS (HR 0.49, 95% CI 0.34–0.70), as well as in PFS (HR 0.37, 95% CI 0.25–0.54) [ 28 ]. The most common treatment-related adverse event (TRAE) was ascites, seen in 11 (9%) treated patients and 4 (7%) in the placebo arm, while their quality of life appeared unchanged.…”