MYC-Mediated Functional Manifestation of IDH1 Mutations in Intrahepatic Cholangiocarcinoma Confers Sensitivity to (+)-JQ1

Intrahepatic cholangiocarcinoma (ICC) is one of most aggressive malignancies attributable to limited treatment options. IDH1 is commonly mutated and frequently cooccurred with other genetic alterations in ICC. The mechanism by which they affect ICC patient prognosis and therapeutic resistance remains incompletely understood. We aimed to investigate the function of MYC in IDH1mutant ICC progression and develop the novel therapeutic strategies. We well-established spontaneous ICC mouse models using transposon-based Idh1 and Kras mutations system in liver-specific knockout Trp53 mice. We generated multiple independent primary ICC cells and organoids derived from tumor tissues and established subcutaneous allograft ICC tumors. Together, multiple models in our studies were utilized to elucidate the role of MYC in IDH1-mutant ICC progression and to investigate therapeutic strategies. We demonstrated that the IDH1 mutations correlated with a favorable outcome in ICC patients and murine models. However, MYC overexpression drove the malignant phenotypic manifestation of Idh1 mutations, reversing this phenotype. Mechanistically, Idh1-mutant ICC reprogrammed glutamine metabolism to regulate Myc expression. Notably, ICC with concurrent IDH1 mutations and MYC amplification exhibited sensitivity to the MYC inhibitor (+)-JQ1, but remained resistant to the IDH1 mutation inhibitor AG120. This study identified MYC as a critical pathogenic driver of malignant progression in IDH1-mutant ICC. MYC overexpression conferred resistance to IDH1 mutation inhibitor, while creating a therapeutic vulnerability to MYC-targeted agents. The selective efficacy of (+)-JQ1 against IDH1-mutant ICC identified MYC inhibition as a promising precision medicine strategy for this molecular subset.