RMC-7977 is a broad-spectrum inhibitor of RAS-GTP, showing potent anti-tumor activity in pancreatic ductal adenocarcinoma (PDAC) models. It selectively targets active GTP-bound forms of KRAS, HRAS, and NRAS, with efficacy in KRAS-mutated PDAC, which accounts for over 90% of PDAC cases. RMC-7977 demonstrated significant tumor growth inhibition in multiple PDAC models, including xenograft and allograft models, with minimal toxicity. In vivo studies showed that RMC-7977 extended survival in KPC mouse models, although relapse occurred, with resistance mechanisms such as Myc copy number gain identified. Combinatorial TEAD inhibition could overcome this resistance. RMC-7977 selectively inhibited RAS signaling in PDAC, inducing apoptosis and reducing proliferation, while normal tissues showed only transient effects. The pharmacokinetic profile of RMC-7977 showed higher concentrations in tumor tissues compared to blood, suggesting effective targeting of RAS in PDAC. Resistance mechanisms included Myc copy number gain and YAP-TAZ pathway activation, which could be counteracted by TEAD inhibitors. These findings support the use of broad-spectrum RAS-GTP inhibitors in PDAC, with potential for combination therapies to overcome resistance. The study highlights the tumor-selective activity of RAS-GTP inhibitors and their potential in treating RAS-addicted cancers.RMC-7977 is a broad-spectrum inhibitor of RAS-GTP, showing potent anti-tumor activity in pancreatic ductal adenocarcinoma (PDAC) models. It selectively targets active GTP-bound forms of KRAS, HRAS, and NRAS, with efficacy in KRAS-mutated PDAC, which accounts for over 90% of PDAC cases. RMC-7977 demonstrated significant tumor growth inhibition in multiple PDAC models, including xenograft and allograft models, with minimal toxicity. In vivo studies showed that RMC-7977 extended survival in KPC mouse models, although relapse occurred, with resistance mechanisms such as Myc copy number gain identified. Combinatorial TEAD inhibition could overcome this resistance. RMC-7977 selectively inhibited RAS signaling in PDAC, inducing apoptosis and reducing proliferation, while normal tissues showed only transient effects. The pharmacokinetic profile of RMC-7977 showed higher concentrations in tumor tissues compared to blood, suggesting effective targeting of RAS in PDAC. Resistance mechanisms included Myc copy number gain and YAP-TAZ pathway activation, which could be counteracted by TEAD inhibitors. These findings support the use of broad-spectrum RAS-GTP inhibitors in PDAC, with potential for combination therapies to overcome resistance. The study highlights the tumor-selective activity of RAS-GTP inhibitors and their potential in treating RAS-addicted cancers.