PKMYT1 is a Targetable Vulnerability in del(17p) High-Risk Multiple Myeloma
Abstract
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.
Article Details
Authors (19)
Anaïs Schavgoulidze
Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
Jian Cui
Jessica Encinas
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., United States
Vanessa Katia Favasuli
Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy
Srikanth Talluri
DFCI, Boston, Massachusetts, United States
Sabrina Mahéo
IUCT, TOULOUSE, France
Chloe Cerutti
Institut Universitaire du Cancer de Toulouse-Oncopole, 31100, France
Masood A Shammas
Dana Farber Cancer Institute, Boston, Massachusetts, United States
Daniel Primo
Vivia Biotech, Madrid, Spain
Carmen Vicente
University of Navarra, Pamplona, Spain
Marta Larrayoz
Jose A Martínez-Climent
Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Kenneth C. Anderson
Anil Aktas Samur
Dana Farber Cancer Institution, Boston, Massachusetts, United States
Mehmet K. Samur
Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts, United States
Hervé Avet-Loiseau
Unité Génomique du Myélome, Hôpital Universitaire de Toulouse Oncopole, Université de Toulouse, Toulouse, France
Jill Corre
Unité Génomique du Myélome, Hôpital Universitaire de Toulouse Oncopole, Université de Toulouse, Toulouse, France
Nikhil C. Munshi
Mariateresa Fulciniti
Dana Farber Cancer Institute, Boston, Massachusetts, United States