Comprehensive CRISPR-Cas9 screens identify genetic determinants of drug responsiveness in multiple myeloma

Abstract The introduction of new drugs in the past years has substantially improved outcome multiple myeloma (MM). However, majority patients eventually relapse and become resistant to one or drugs. While genetic landscape relapsed/ been elucidated, causal relationship between relapse-specific gene mutations sensitivity a given drug MM not systematically evaluated. To determine functional impact mutations, we performed combined whole-exome sequencing (WES) longitudinal patient samples with CRISPR-Cas9 resistance screens for lenalidomide, bortezomib, dexamethasone, melphalan. WES from 16 identified large number each that were newly acquired evolved small subclone (median 9, range 1-55), including recurrent TP53, DNAH5, WSCD2. Focused against 170 functionally linked 15 them resistance. These included cereblon E3 ligase complex members structural genes PCDHA5 ANKMY2 RB1 CDK2NC TP53 In contrast, inactivation involved DNA damage repair pathway, ATM, FANCA, RAD54B, BRCC3, enhanced susceptibility cytotoxic chemotherapy. Resistance patterns highly specific low overlap correlated treatment-dependent clonal evolution patients. association alterations will help personalize treatment future.