Multi-omic and functional screening reveal targetable vulnerabilities in TP53 mutated multiple myeloma

Despite development of several effective therapies for multiple myeloma (MM), the prognosis of patients with partial deletion of chromosome 17 (del(17p)) and TP53 aberrations remains poor. By applying comprehensive multi-omics profiling analyses (whole exome and transcriptome sequencing plus proteomics) and functional ex vivo drug screening to samples from 167 patients with MM, we uncovered novel therapeutic vulnerabilities specific to TP53 mutated MM. Our findings revealed a distinct sensitivity profile to a range of inhibitors (mitotic, topoisomerase, HDAC, HSP90, IGF1R and PI3K/AKT/mTOR inhibitors) irrespective of 17p deletion status. Conversely, no increase in sensitivity was observed for monoallelic TP53 (del(17p) with WT TP53) when compared to WT TP53 samples, highlighting the remaining unmet clinical need. Notably, plicamycin, an RNA synthesis inhibitor linked to modulation of chromatin structure and increased transcription, emerged as particularly efficacious for TP53 mutated MM. The increased sensitivity correlated with higher protein expression of the drug targets: HDAC2, HSP90AA1 and multiple ribosomal subunits. Additionally, we observed increased RNA expression of G2M checkpoint, E2F targets and mTORC1 signaling in our cohort and the MMRF-CoMMpass (NCT01454297) study in TP53 mutated MM. Harmonization of multi-omics data with ex vivo drug screening results revealed that TP53 mutated MM is functionally distinct from MM with monoallelic TP53, and demonstrates that MM with mutated TP53, with and without del(17p), may be targetable by approved drugs. These results further indicate the need for regular monitoring by sequencing to identify these patients. KEY POINTSTP53 mutation in myeloma confers sensitivity to multiple compounds, including approved drugs, irrespective of del(17p) status. TP53 mutated myeloma links to higher expression of drug targets involved in cell proliferation, mRNA processing, and chromatin modulation.