Supplementary Figure S1-S6 from Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers

Supplementary Figure 1 shows RMC-6236 crystal structure in tri-complex, as well as biophysical and cellular potencies of RMC-6236 by genotype. Supplementary Figure 2 shows RMC-6236 demonstrates dose-dependent anti-tumor activities at tolerable doses; and pharmacodynamic effects on RAS signaling in NCI-H441 xenograft tumors as assessed by IHC, and in relatively refractory KP-4 and NCI-H2122 xenograft tumors as assessed by human DUSP6 mRNA expression in vivo. Supplementary Figure 3 shows genotype dependent response of RMC-6236 across NSCLC, PDAC and CRC; and potential modifiers to the durability of response of KRASG12C NSCLC models upon RMC-6236 treatment assessed by Kaplan-Meier analyses. Supplementary Figure 4 shows Efficacy of RMC-6236 on KrasG12C–driven autochthonous lung tumors harboring cis second-site mutations within KrasG12C (KrasG12C,H95D or KrasG12C,Y96C) and eCT26 (KrasG12D/G12D) syngeneic model in immunocompetent mice; anti-tumor immunity of RMC-6236; and in intracranially implanted NCI-H1373-Luc xenograft model on nude mice. Supplementary Figure 5 shows effects of RMC-6236 mediated pharmacological modulation in KP-4 xenograft tumors and normal colon tissues isolated from xenograft tumor bearing mice. Supplementary Figure 6 shows a graphical representation of the combined mouse PK-Efficacy and PK/PD model.