Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance

Supplementary Table 10 - 13 from Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression

Supplementary Table 10: Antibodies for IHC and IF.Overview of antibodies used for stainings in human PDAC or KPC-derived tissues.Supplementary Table 11: Primer sequences for qRT-PCR.Primers for qRT-PCR-based quantification of ChIP and mRNA samples.Supplementary Table 12: Freezer dryer settings for sponge production.Specific settings for optimal sponge production.Supplementary Table 13: Explant media composition.List of reagents used for human PDAC and murine explants.</p

Supplementary Table 8 from Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression

Lymphoid network.Regulatory network for PDAC-associated lymphoid cells, listing the inferred transcriptional targets (Target) for each regulatory protein (Regulator). Association weight (AW) and association mode (AM) are scores to quantify strength/direction of interaction. Sign indicates directionality of the interaction (1 = transactivating, -1 = transrepressing).</p

Supplementary Table 5 from Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression

Endothelial network.Regulatory network for PDAC-associated endothelial cells, listing the inferred transcriptional targets (Target) for each regulatory protein (Regulator). Association weight (AW) and association mode (AM) are scores to quantify strength/direction of interaction. Sign indicates directionality of the interaction (1 = transactivating, -1 = transrepressing).</p

Supplementary Figure 7 from Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression

WNT Distribution and Expression of Downstream Targets.</p

Supplementary Figure 3 from Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression

Explant cellular populations.</p

Supplementary Table 6 from Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression

Epithelial network.Regulatory network for PDAC-associated epithelial cells, listing the inferred transcriptional targets (Target) for each regulatory protein (Regulator). Association weight (AW) and association mode (AM) are scores to quantify strength/direction of interaction. Sign indicates directionality of the interaction (1 = transactivating, -1 = transrepressing).</p

Supplementary Table 5 from Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression

Endothelial network.Regulatory network for PDAC-associated endothelial cells, listing the inferred transcriptional targets (Target) for each regulatory protein (Regulator). Association weight (AW) and association mode (AM) are scores to quantify strength/direction of interaction. Sign indicates directionality of the interaction (1 = transactivating, -1 = transrepressing).</p

Supplementary Table 9 from Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression

Myeloid network.Regulatory network for PDAC-associated myeloid cells, listing the inferred transcriptional targets (Target) for each regulatory protein (Regulator). Association weight (AW) and association mode (AM) are scores to quantify strength/direction of interaction. Sign indicates directionality of the interaction (1 = transactivating, -1 = transrepressing).</p

Supplementary Figure 7 from Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression

WNT Distribution and Expression of Downstream Targets.</p