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

Nature. 2024 May;629(8013):927-936. doi: 10.1038/s41586-024-07379-z. Epub 2024 Apr 8.


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.

MeSH terms

  • Animals
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Apoptosis / drug effects
  • Carcinoma, Pancreatic Ductal* / drug therapy
  • Carcinoma, Pancreatic Ductal* / genetics
  • Carcinoma, Pancreatic Ductal* / metabolism
  • Carcinoma, Pancreatic Ductal* / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Copy Number Variations
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Genes, myc
  • Guanosine Triphosphate* / metabolism
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mutation
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / genetics
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / metabolism
  • Pancreatic Neoplasms* / pathology
  • Proto-Oncogene Proteins p21(ras)* / antagonists & inhibitors
  • Proto-Oncogene Proteins p21(ras)* / genetics
  • Proto-Oncogene Proteins p21(ras)* / metabolism
  • Treatment Outcome
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Guanosine Triphosphate
  • HRAS protein, human
  • KRAS protein, human
  • NRAS protein, human
  • Proto-Oncogene Proteins p21(ras)