Integrated FHIT and IDH2 biomarkers predict synthetic lethal response to DCPS inhibition in acute myeloid leukemia

DCPS (Decapping Scavenger Enzyme) is a critical regulator of RNA metabolism that clears cap structures generated during mRNA decay. At Sprint Bioscience, in the frame of our efforts to develop new modalities in oncology, we have generated, among others, novel selective DCPS inhibitors (DCPSi) with sub-nanomolar activity in cells using our fragment- and structure-based drug discovery platform. Using the clinically validated DCPSi RG3039 across a panel of AML cell models, we identified a synthetic lethal interaction between DCPS and the cap-degrading enzyme Fragile Histidine Triad (FHIT), which shares overlapping substrate specificity. In both in vivo and ex vivo systems, low FHIT expression emerged as a strong predictive biomarker of therapeutic response to DCPSi, while hydroxyurea pretreatment was identified as a negative confounding factor. Mechanistically, FHIT loss preserves the therapeutic effects of DCPSi, including release of differentiation blockade, induction of cell-cycle arrest, and apoptosis-key vulnerabilities in AML. Interrogation of AML databases (cBioPortal OHSU 2022, total 942 samples) and primary patient samples (Champions Oncology, 30 ex vivo unpassaged primary AML ) further revealed that IDH2 mutation status correlates with both FHIT expression (FDR=0.002) and sensitivity to DCPSi (p=0.042), identifying IDH2 as an additional predictive biomarker. Primary AML specimens harboring IDH2 mutations demonstrated increased susceptibility to RG3039, consistent with this molecular association. Together, these findings establish DCPS as a safe and efficacious therapeutic target in AML. We propose that FHIT expression, frequently reduced in cancer, provides a biomarker-driven strategy for patient stratification, and that IDH2 mutation status further refines prediction of response to DCPS-targeted therapy.