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

James M Cleary; Betty Rouaisnel; Antoine Daina; Srivatsan Raghavan; Lauren A Roller; Brandon M Huffman; Harshabad Singh; Patrick Y Wen; Nabeel Bardeesy; Vincent Zoete; Brian M Wolpin; Julie-Aurore Losman

doi:10.1038/s41698-022-00304-5

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

NPJ Precis Oncol. 2022 Sep 2;6(1):61. doi: 10.1038/s41698-022-00304-5.

Authors

Affiliations

¹ Dana-Farber/Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. james_cleary@dfci.harvard.edu.
² Dana-Farber/Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
³ SIB Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, Switzerland.
⁴ Brigham and Women's Hospital, Department of Radiology, Harvard Medical School, Boston, MA, USA.
⁵ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
⁶ University of Lausanne, Department of Oncology UNIL-CHUV, Ludwig Lausanne Branch, Lausanne, Switzerland.
⁷ Dana-Farber/Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. julieaurore_losman@dfci.harvard.edu.
⁸ Brigham and Women's Hospital, Department of Medicine, Division of Hematology, Harvard Medical School, Boston, MA, USA. julieaurore_losman@dfci.harvard.edu.

^# Contributed equally.

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.

Grants and funding

P50 CA127003/CA/NCI NIH HHS/United States