Slide 1: Tri-Complex Inhibitors of the Oncogenic, GTP-Bound Form of KRAS G12C Overcome RTK-Mediated Escape
Tri-Complex Inhibitors of the Oncogenic, GTP-Bound Form of KRASG12C Overcome RTK-Mediated Escape Mechanisms and Drive Tumor Regressions in Vivo Chris Schulze, Ph.D. Revolution Medicines © 2019 Revolution Medicines
Slide 2: Disclosure Information
Disclosure Information AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Speaker: Chris Schulze I have the following financial relationships to disclose: Employee of: Revolution Medicines I will not discuss off label use and/or investigational use in my presentatio
Slide 3: RAS(ON) – the Active, GTP-Bound Form of RAS – Regulates Cell Growth and Survival
RAS(ON) – the Active, GTP-Bound Form of RAS – Regulates Cell Growth and Survival RAS(OFF) Switch region SOS1 RAS(ON) GDP GTP NF1 Cell growth and survival effectors 3
Slide 4: Tri-Complex Inhibitor Modality for Difficult Drug Targets, Inspired by Nature’s Innovation
Tri-Complex Inhibitor Modality for Difficult Drug Targets, Inspired by Nature’s Innovation EVOLUTION REVOLUTION RAS(ON) mTOR Drug FKBP12 Chaperone Tri-Complex Rapamycin (Everolimus) 4
Slide 5: KRAS G12C (ON) Inhibitors: Induced Binding Site and Differentiated Mode of Inhibition
KRASG12C(ON) Inhibitors: Induced Binding Site and Differentiated Mode of Inhibition KRASG12C(ON) High affinity for KRASG12C(ON), Induced the oncogenic pocket form of KRASG12C Cyclophilin A 5
Slide 6: Tri-Complex Directly Prevents RAF Engagement by Blocking Effector Face of KRAS G12C(ON)
Tri-Complex Directly Prevents RAF Engagement by Blocking Effector Face of KRASG12C(ON) 100 RAS-RAF RAS-RAF Disruption (%) Disruption 75 50 KRASG12C(ON) 25 0 -10 -9 -8 -7 -6 -5 NCI-H358 RAF Cellular pERK log M [RM-10] (RBD) Steric occlusion NCI-H358 Cyclophilin A Cell proliferation (2D, 5 day) Layere
Slide 7: KRAS G12C (ON) Inhibitor Prototype Drives Tumor Xenograft Regressions in Vivo
KRASG12C(ON) Inhibitor Prototype Drives Tumor Xenograft Regressions in Vivo NCI-H358 CDX (NSCLC, KRASG12C) Tumor lysate target Control RM-010 100 mg/kg ip qd engagement Total RAS 8 Days Post-Implant End of study responses N = number of regressions >10% at end of study (EOS) 7
Slide 8: KRAS G12C (ON) Inhibitor Dosed Weekly with Daily SHP2 Inhibitor Drives Xenograft Regressions
KRASG12C(ON) Inhibitor Dosed Weekly with Daily SHP2 Inhibitor Drives Xenograft Regressions NCI-H358 CDX (NSCLC, KRASG12C) Control SHP2 Inhibitor 30 mg/kg po qd RMC-011 60 mg/kg iv qw Combination 5 1 8 Days Post-Implant End of study responses 8
Slide 9: KRAS G12C (ON) Lead Series Compound Drives Tumor Xenograft Regressions in Vivo
KRASG12C(ON) Lead Series Compound Drives Tumor Xenograft Regressions in Vivo NCI-H358 CDX (NSCLC, KRASG12C) MIA PaCa-2 CDX (PDAC, KRASG12C) Control Control RM-015 10 mg/kg ip qd RM-015 30 mg/kg ip qd RM-015 30 mg/kg ip qd Days Post-Implant Days Post-Implant 5 10 10 9 End of study responses End of st
Slide 10: MEK Inhibition Drives High Levels of RAS(ON)
MEK Inhibition Drives High Levels of RAS(ON) SHP2 SHP2 SOS1 SOS1 GDP GDP GTP GTP RAS(OFF) RAS(ON) RAS(OFF) RAS(ON) NF1 NF1 RAF RAF MEK MEK MEK inhibition Loss of negative feedback ERK ERK Growth, Growth, Survival Survival 10
Slide 11: Inhibitors Combine With MEK Inhibitor to Suppress in Vitro Growth Durably
KRASG12C(ON) Inhibitors Combine With MEK Inhibitor to Suppress in Vitro Growth Durably Long-Term Cell Growth (NCI-H358, KRASG12C) KRASG12C(OFF) KRASG12C(ON) DMSO Trametinib DMSO Trametinib 100 100 MRTX-1257 RM-010 % Confluence % Confluence Combination 50 50 Combination 0 0 0 10 20 30 40 0 10 20 30 4
Slide 12: KRAS G12C (ON) Inhibitor Drives Tumor Xenograft Regressions in Combination with MEK Inhibitor
KRASG12C(ON) Inhibitor Drives Tumor Xenograft Regressions in Combination with MEK Inhibitor NCI-H358 CDX (NSCLC, KRASG12C) Control Cobimetinib 2.5 mg/kg po qd RM-015 50 mg/kg iv biw Combination 0 0 6 Days Post-Implant End of study responses 12
Slide 13: RAS Hotspot Hopping: Inhibitors of KRAS G13C(ON)
RAS Hotspot Hopping: Inhibitors of KRASG13C(ON) NCI-H1734 (KRASG13C) covalent NCI-H1734 (KRASG13C) pERK target engagement KRASG13C(ON) X-linked RAS Total RAS 13
Slide 14: Conclusions
Conclusions • Tri-complex RAS(ON) inhibitors cause steric occlusion of the effector face of RAS and inhibit oncogenic signaling by RAS mutants • Tri-complex inhibitors drive tumor regressions in KRASG12C xenografts • RAS(ON) inhibitors are less susceptible to resistance driven by upstream pathway ac