Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited genomic and proteomic profiles, particularly in Asian populations. This study provides a comprehensive characterization of Chinese ACC patients, identifying unique genomic features, exploring the pathogenesis of isocitrate dehydrogenase 1 (IDH1)-mutated ACC, and uncovering potential therapeutic targets.

Sixty-five ACC cases from three centers underwent Integrated genomic and proteomic analyses, including exome sequencing (45 tumors), SNP array (45 tumors), proteomics (45 tumors), spatial transcriptomics, and proteomics (4 tumors). Gene Set Variation Analysis (GSVA) was applied using gene sets from MSigDB (e.g., HALLMARK_HYPOXIA and HALLMARK_GLYCOSIS). GSVA scores were mapped onto slides using the scanpy function sc.pl.spatial, allowing the delineation of four metabolic regions based on glycolysis and hypoxia levels: GlycosishighHypoxiahigh, GlycosishighHypoxialow, GlycosislowHypoxiahigh, GlycosislowHypoxialow. These regions were isolated by laser-capture microdissection followed by high-sensitivity mass spectrometry to spatially define the proteomic profiles. Patient-derived xenografts (PDXs) were established by grafting IDH1-mutated tumors under the renal capsules of NSG mice. Mice were administered either vehicle, ivosidenib (75 mg/kg orally), or a combination of ivosidenib and ganitumab (3 mg/mL, i.p.) twice a week.

Frequent mutations were detected in known driver genes (CTNNB1, TP53, MEN1) and previously unreported genes in ACC, such as IDH1 and IDH2. Mutations in IDH1 (28.9%) and IDH2 (40%) were significantly more prevalent in our cohort than in the TCGA (0%) and COSMIC (0%) datasets, which primarily include Caucasian patients. We have enrolled one case with metastatic ACC harboring an IDH1 mutation who achieved a partial response and exhibited 13 months of progression-free survival and 32 months of overall survival after treatment with ivosidenib, an IDH1 inhibitor. Ethical Committee approval was obtained from the Second Affiliated Hospital of Kunming Medical University. Spatial transcriptomics revealed that IDH1-mutated tumors were characterized by activation of glycolysis and hypoxia pathways. Spatial proteomic analysis across the four defined regions identified IGF-1R as the most upregulated protein in the GlycosishighHypoxiahigh region. In PDX models, combined therapy with IDH1 inhibitor (ivosidenib) and IGF-1R inhibitor (ganitumab) showed superior efficacy over monotherapy.

IDH1 mutations are highly prevalent in Chinese ACC patients and are associated with glycolysis and hypoxia activation, leading to IGF-1R signaling upregulation. Our preclinical findings support a combination of ivosidenib and ganitumab as a promising treatment for IDH1-mutated ACC.