Biomarkers in the ERA of precision medicine: Characterizing MOA for targeted therapies using single-cell multiomics in the clinic

Myeloproliferative neoplasms (MPNs) driven by mutCALR present a clear therapeutic target, yet validating the in vivo mechanism of action (MOA) of new drugs like INCA033989 is a major challenge. Traditional bulk sequencing is critically insufficient, as it masks heterogeneous responses and cannot resolve the drug's effect on specific hematopoietic lineages. To overcome this, the deployment of a single-cell multiomic assay was essential. By combining scDNA-seq and immunophenotyping, clinical phase 1 studies (NCT05936359, NCT06034002) provided the first definitive, cell-type-specific evidence of INCA033989's activity. It uniquely demonstrated a profound, selective eradication of mutCALR+ hematopoietic stem/progenitor (HSPC) and myeloid populations, an insight impossible to gain from bulk analysis. This single-cell validation, which also captured the expansion of wild-type (WT) cells, confirms the INCA033989 mechanism of action (MOA) and highlights the necessity of single-cell multiomic assays for developing modern targeted therapies.