Reference Detail

Ref Type

Journal Article

PMID

(36056177)

Authors

Cleary JM, Rouaisnel B, Daina A, Raghavan S, Roller LA, Huffman BM, Singh H, Wen PY, Bardeesy N, Zoete V, Wolpin BM, Losman JA

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
NPJ precision oncology	6	1	2022 Sep 02	61	NPJ Precis Oncol

URL

Abstract Text

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
LY3410738	LY3410738	9	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
LY3410738		LY-3410738\|LY 3410738	IDH1 Inhibitor 8	LY3410738 is a covalent inhibitor of mutant IDH1, which may lead to anti-tumor activity in IDH1-mutant tumors (PMID: 36056177).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
IDH1	D279N	missense	unknown	IDH1 D279N does not lie within any known functional domains of the Idh1 protein (UniProt.org). D279N results in cellular transformation in the context of IDH1 R132H (PMID: 36056177) and has been associated with acquired IDH1 inhibitor resistance with IDH1 R132C (PMID: 32380538; PMID: 36056177), but has not been individually characterized and therefore, its effect on Idh1 protein function is unknown (PubMed, Jan 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
IDH1 R132C IDH2 R172K	intrahepatic cholangiocarcinoma	predicted - resistant	Ivosidenib	Case Reports/Case Series	Actionable	In a clinical case study, IDH2 R172K was identified upon progression in a patient with metastatic intrahepatic cholangiocarcinoma harboring IDH1 R132C, along with PIK3CA E545K, who previously responded to Tibsovo (ivosidenib) (PMID: 36056177).	36056177
IDH1 R132H IDH1 D279N	acute myeloid leukemia	predicted - resistant	Ivosidenib	Preclinical - Cell culture	Actionable	In a preclinical study, Tibsovo (ivosidenib) modestly suppressed (R)-2-hydroxyglutarate (R-2HG) production in an acute myeloid leukemia cell line expressing IDH1 R132H and D279N but did not inhibit cytokine-independent growth in culture (PMID: 36056177).	36056177
IDH1 R132H IDH1 D279N	acute myeloid leukemia	sensitive	LY3410738	Preclinical - Cell culture	Actionable	In a preclinical study, LY3410738 inhibited (R)-2-hydroxyglutarate (R-2HG) production and cytokine-independent growth in an acute myeloid leukemia cell line expressing IDH1 R132H and D279N in culture (PMID: 36056177).	36056177
IDH1 R132C IDH1 D279N	intrahepatic cholangiocarcinoma	predicted - resistant	Ivosidenib	Case Reports/Case Series	Actionable	In a clinical case study, IDH1 D279N was identified upon progression in a patient with metastatic intrahepatic cholangiocarcinoma harboring IDH1 R132C, along with NRAS G13V, who previously responded to Tibsovo (ivosidenib) (PMID: 36056177).	36056177