PKMYT1 is a Targetable Vulnerability in del(17p) High-Risk Multiple Myeloma

Deletion of 17p is among the most adverse cytogenetic abnormalities in multiple myeloma (MM). By integrating RNA-seq data from patient MM cells with genetic dependency data from MM cell lines, we identified the protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) kinase, a member of the Wee family, as a potential therapeutic target in MM cells harboring del(17p). Genetic suppression or pharmacological inhibition of PKMYT1 activity with the selective inhibitor RP-6306 triggered accumulation of DNA damage, micronucleus formation and mitotic catastrophe, resulting in preferential cell death in del(17p) MM cells while largely sparing del(17p)-negative MM cells and healthy cells. RP-6306 also reduced tumor burden and extended survival in vivo in both xenograft and TP53-deficient syngeneic models. Collectively, our findings nominate PKMYT1 as an actionable target and support PKMYT1 inhibition as a biomarker-driven therapeutic strategy for patients with del(17p)/TP53-deficient MM.