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. 2020 May 11;10(5):54. doi: 10.1038/s41408-020-0320-7

Fig. 7. Ex vivo drug sensitivity profiles of 70 drugs in 68 patient samples define sample subgroups with differential chemosensitivity and illuminate contextual susceptibilities to MM drugs.

Fig. 7

a Unsupervised hierarchical clustering analysis of drug sensitivities measured by AUCs identified nine drug clusters (rows) defining six major patient clusters (columns, A–F). Group A was sensitive to the most drug classes (mean AUC(A) 0.5697). Groups D and E had intermediate sensitivity (mean AUC(D) 0.6409; mean AUC(E) 0.6761) with very similar chemosensitivity profiles, followed by group F (mean AUC(F) 0.7301). Clusters B and C were the most drug resistant (mean AUC(C) 0.7881; mean AUC(B) 0.8209). The clinical profile, cytogenetic classification, and mutational profile by sample group are annotated above the heatmap and summarized in Supplemental Table 10. Row cluster 1 is enriched in HDAC inhibitors. Row cluster 3 isolated venetoclax as a singleton, revealing the unique drug sensitivity profile of this drug. PIs were grouped in row cluster 4. Row clusters 2, 5, 6, and 9 contained kinase inhibitors targeting ALK, MAPK, EGFR, and PI3K/mTOR, which had enhanced sensitivity in group A as compared to resistant groups B and C. Group A was also more sensitive to DNA synthesis inhibitors and was enriched by later relapse MM samples characterized also by high risk genomic abnormalities including t(4;14) and/or gain of chromosome 1q. The most resistant groups B and C in contrast were enriched for untreated or early relapse samples with high risk stratification. They primarily differed from each other by t(11;14) status (Mann–Whitney test; p = 0.0132) and sensitivity to PIs. HDAC inhibitors and select KIs also had differential chemosensitivity profiles between these two resistant groups (Fig. 8). The three intermediate sensitivity groups (clusters D, E, and F) retained sensitivity to ALK inhibitors and BET inhibitors lost in resistant groups B and C (row cluster 6). (B-C) Box plots of the drug sensitivity (AUCs) by sample subgroup, showing: b Differential sensitivity of selinexor by sample group, with exquisite selinexor sensitivity of samples in cluster A as compared to resistant groups B and C, and to intermediate groups E and F; c Differential sensitivity of venetoclax by sample group, with group A trending as the least sensitive of all.