[slides] Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer

The study evaluates the therapeutic potential of RMC-7977, a broad-spectrum RAS-GTP inhibitor, in pancreatic ductal adenocarcinoma (PDAC). RMC-7977 is highly selective for KRAS, HRAS, and NRAS, targeting both mutant and wild-type variants. Over 90% of PDAC cases are driven by KRAS mutations. The compound exhibited broad and pronounced anti-tumour activity across various PDAC models, with well-tolerated exposures in vivo. Pharmacological analyses revealed that RMC-7977 induced apoptosis and sustained proliferative arrest in tumours, while normal tissues showed only transient decreases in proliferation without apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment significantly extended survival but led to relapse, which was associated with Myc copy number gain as a resistance mechanism. Combining RMC-7977 with TEAD inhibition overcomeed this resistance. These findings establish a strong preclinical rationale for broad-spectrum RAS-GTP inhibition in PDAC and suggest a promising combination therapeutic regimen to address monotherapy resistance.The study evaluates the therapeutic potential of RMC-7977, a broad-spectrum RAS-GTP inhibitor, in pancreatic ductal adenocarcinoma (PDAC). RMC-7977 is highly selective for KRAS, HRAS, and NRAS, targeting both mutant and wild-type variants. Over 90% of PDAC cases are driven by KRAS mutations. The compound exhibited broad and pronounced anti-tumour activity across various PDAC models, with well-tolerated exposures in vivo. Pharmacological analyses revealed that RMC-7977 induced apoptosis and sustained proliferative arrest in tumours, while normal tissues showed only transient decreases in proliferation without apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment significantly extended survival but led to relapse, which was associated with Myc copy number gain as a resistance mechanism. Combining RMC-7977 with TEAD inhibition overcomeed this resistance. These findings establish a strong preclinical rationale for broad-spectrum RAS-GTP inhibition in PDAC and suggest a promising combination therapeutic regimen to address monotherapy resistance.