Molecular classification identifies aggressive gastrointestinal stromal tumor subtype targetable by PARP inhibitors

PURPOSE: Gastrointestinal stromal tumors (GISTs), the most common gastrointestinal sarcomas, experience a high rate of resistance to standard treatment tyrosine kinase inhibitor (TKI) imatinib, leading to tumor progression. Identifying non-responders and offering precise alternatives are crucial, however, multi-omics studies of GIST are limited, which hinders GIST biology understanding and novel drug development. METHODS: We performed whole-exome and transcriptomic sequencing on 106 primary GIST patients. Subtype-specific molecular features and therapeutic responses were further validated in vitro and in vivo. RESULTS: Unsupervised clustering analysis of RNA data classified them into four subtypes, including immune (G1), stromal (G2), proliferative (G3), and metabolic (G4) subtypes. The G4 subtype had more patients with primary non-gastric tumors, a poor response to neoadjuvant imatinib treatment and synchronous metastasis, with an overall poor prognosis. Notably, G4 subtype exhibited significantly enhanced aerobic metabolism. Moreover, G4 subtype harbored homologous recombination repair deficiency (HRD) signatures, with significantly reduced homologous recombination activity and upregulation of non-homologous repair pathways. By stratifying GIST cell lines into subtypes, we confirmed that the HRD-targeting poly ADP-ribose polymerase (PARP) inhibitor Olaparib suppressed tumor growth in the G4 subtype-representative GIST882 cell line. In vivo experiments demonstrated that Olaparib monotherapy significantly reduced tumor burden in GIST882 xenograft-bearing mice and synergized with imatinib. CONCLUSION: We systematically deconstructed the molecular subtypes of primary GISTs by integrated genomic and transcriptomic analysis. A specific GIST subtype characterized by poor treatment responses and prognosis, marked by the activation of aerobic metabolism and HRD features, may be a potential candidate for PARP inhibitors.