A novel BCMA PBD-ADC with ATM/ATR/WEE1 inhibitors or bortezomib induce synergistic lethality in multiple myeloma

摘要: To target mechanisms critical for multiple myeloma (MM) plasma cell adaptations to genomic instabilities and further sustain MM killing, we here specifically trigger DNA damage response (DDR) in cells by a novel BCMA antibody-drug conjugate (ADC) delivering the DNA cross-linking PBD dimer tesirine, MEDI2228. MEDI2228, more effectively than its anti-tubulin MMAF-ADC homolog, induces cytotoxicity against regardless of drug resistance, levels, p53 status, protection conferred bone marrow stromal IL-6. Distinctly, prior apoptosis, MEDI2228 activates DDRs via phosphorylation ATM/ATR kinases, CHK1/2, CDK1/2, H2AX, associated with expression DDR-related genes. Significantly, synergizes DDR inhibitors (DDRi s) targeting ATM/ATR/WEE1 checkpoints induce lethality. Moreover, suboptimal doses bortezomib (btz) synergistically apoptosis even drug-resistant partly modulation RAD51 accumulation impaired DNA. Such combination superior vivo efficacy monotherapy increased nuclear γH2AX-expressing foci, irreversible damages,  tumor death, leading significantly prolonged host survival. These results indicate leveraging DDRi s or btz as strategies, supporting ongoing clinical development patients relapsed refractory MM.