Figure 6: Anti-tumor activity of combined ERK1/2 and CDK4/6 inhibition in PDX models.

Growth kinetics of DFCI168^NRASQ61K (A) and DFCI24^KRASG12C (B) tumors treated with vehicle, LY3214996 (100mg/kg, PO QD), abemaciclib (50mg/kg, PO QD) or a combination of both drugs for 28 days (n=8-10/group; Two-way Repeated Measures ANOVA with standard post hoc t-tests). Waterfall plots of individual tumor responses are depicted for day 29 (DFCI168) and day 15 (DFCI24), respectively (PD - progressive disease (solid columns); SD - stable disease (pattern columns); PR - partial response (open colums); CR - complete response (pink column)). (C) Tumor growth delay (in days) in mice xenotransplanted with DFCI168^NRASQ61K and DFCI24 tumors by treatment regimen compared to vehicle treated animals. (TGI – Tumor Growth Inhibition) (D) Western blot analysis of lysates of DFCI168^NRASQ61K tumors treated with vehicle, LY3214996 (100mg/kg, QD), abemaciclib (50mg/kg, QD) or a combination of both drugs 4, 8 and 24 h after the last drug application. (E) Pooled mean expression of MAPK pathway-dependent genes (compared to vehicle) in DFCI168^NRASQ61K tumors treated for 4, 8 and 24 h with LY3214996 (100mg/kg), abemaciclib (50mg/kg) or a combination of both drugs (n=3 tumors/group, Student’s t-Test). (F) Schematic summary of the different treatment approaches investigated in this study: single agent LY3214996 treatment for ERK inhibitor sensitive cell lines, combined ERK plus PI3K inhibitor treatment for PI3K pathway-activated ERK inhibitor-resistant cell lines and combined ERK plus CDK4/6 inhibition. The figure was created with BioRender.com.