Fig. 1. OT-resistant SCLC models show a massive increase in tumor mutational burden after relapse.

(A) Schematized clinical histories and in vivo responses to OT of serial PDX models. Models from patients before treatment with OT (blue) and again at progression after a durable clinical response (orange), with vehicle-treated xenografts (gray). Average response in vivo to OT across three to six xenografts as percentage of ITV versus days after treatment (solid line) ± SEM (dashed lines). (B) Venn diagrams were constructed by comparing the shared and unique somatic variants of sequential biopsies. Coding somatic variants were identified as nonsynonymous mutations that fall within a coding region. (C and D) Three-dimensional bar plots (also called “Lego plots”) representing mutational signatures in a three-base context. (D) Left: Mutational signature identified in sensitive models showing C-to-A transversions that are associated with tobacco smoking [SBS4 in COSMIC (82)]. (D) Right: Mutational signature identified in resistant models containing tobacco smoking–associated mutations in addition to large numbers of C-to-T transitions associated with TMZ treatment [SBS11 in COSMIC (82)]. Axes and plots are not in scale, and smoking-associated mutations, which are still present in postrelapse PDXs, are overshadowed by the predominant TMZ signature.