Fig. 6

CDC7 inhibition dramatically sensitizes de novo SCLC PDX to first and second line chemotherapy. In vitro synergy assays in H82 (SCLC-N, left) and H146 (SCLC-A, right) cell lines of the combination of simurosertib and cisplatin or irinotecan (a), or in Lx1042 (T-SCLC) and H660 (NEPC) with the combination of simurosertib and cisplatin (b), with average synergy score displayed, as assessed by Highest Single Agent (HSA) method, and calculated using SynergyFinder. Representative plots are shown. In vivo treatments of high (Lx1231, SCLC-A), intermediate (Lx33, SCLC-N) and low (Lx276, SCLC-A) CDC7-expressing PDX derived from treatment-naïve tumors (c), of high (Lx761c, SCLC-N), intermediate (Lx674c, SCLC-A) and low (Lx95, SCLC-A) CDC7-expressing PDX derived from tumors progressed on chemotherapy (d), and of NE-transformed PDX (Lx1042 and H660)(e), to compare the efficacy of the combination of simurosertib with cisplatin versus that of cisplatin and etoposide (chemotherapy-naïve PDX, including NE-transformed PDX) or of simurosertib with irinotecan versus irinotecan alone (progressed on treatment PDX). p-values for (a), (d), and (e) were calculated using the Student’s t-test (unpaired, heterogeneous variances, two-tailed). p-value legend: *<0.05, **<0.01, ***<0.001