Using CRISPR-Cas 9 screens, researchers were able to identify genetic determinants of response and resistance to commonly used drugs to treat multiple myeloma (MM).
This study was published in Blood Advances.
“While the genetic landscape of relapsed/[refractory] MM has been elucidated, the causal relationship between relapse-specific gene mutations and the sensitivity to a given drug in MM has not systematically been evaluated,” wrote the authors.
The investigators performed combined whole-exome sequencing with CRISPR-Cas9–based drug resistance screens for 16 patients with MM. Sequencing was performed at diagnosis and at least one time during disease progression, for 38 total samples. The drugs evaluated in the CRISPR-Cas9 resistance screens included lenalidomide, bortezomib, dexamethasone, and melphalan. Across the patient cohort, 16 patients (100%) were treated with lenalidomide, 9 (56%) were treated with bortezomib, 16 (100%) received dexamethasone, and 14 (88%) received melphalan.
The investigators reported a high degree of interindividual genetic heterogeneity, with 17 recurrent mutations in ≥2 patients, including KRAS, NRAS, BRAF, DIS3, and IGLL5. Fifteen mutations were functionally linked to drug resistance, cereblon E3 ligase complex members for lenalidomide, PCDHA5 and ANKMY2 for dexamethasone, RB1 and CDK2NC for bortezomib, and TP53 for melphalan. The investigators also reported that inactivation of genes in the DNA damage repair pathway, such as ATM, FANCA, RAD54B, and BRCC3, were linked to increased efficacy of cytotoxic chemotherapy.
In conclusion, the authors wrote, “Resistance patterns were highly drug specific with low overlap and highly correlated with the treatment-dependent clonal evolution in patients. The functional association of specific genetic alterations with drug sensitivity will help to personalize treatment of MM in the future.”