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Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.
- Source :
-
Nature [Nature] 2024 May; Vol. 629 (8013), pp. 927-936. Date of Electronic Publication: 2024 Apr 08. - Publication Year :
- 2024
-
Abstract
- Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations <superscript>1,2</superscript> . 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 variants <superscript>3</superscript> . More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS <superscript>4</superscript> . 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.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Female
Humans
Mice
Apoptosis drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Disease Models, Animal
DNA Copy Number Variations
Drug Resistance, Neoplasm drug effects
Genes, myc
Mice, Inbred BALB C
Mice, Inbred C57BL
Neoplasm Recurrence, Local drug therapy
Neoplasm Recurrence, Local genetics
Treatment Outcome
Xenograft Model Antitumor Assays
Mutation
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Carcinoma, Pancreatic Ductal drug therapy
Carcinoma, Pancreatic Ductal pathology
Carcinoma, Pancreatic Ductal genetics
Carcinoma, Pancreatic Ductal metabolism
Guanosine Triphosphate metabolism
Pancreatic Neoplasms drug therapy
Pancreatic Neoplasms pathology
Pancreatic Neoplasms genetics
Pancreatic Neoplasms metabolism
Proto-Oncogene Proteins p21(ras) genetics
Proto-Oncogene Proteins p21(ras) metabolism
Proto-Oncogene Proteins p21(ras) antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 629
- Issue :
- 8013
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 38588697
- Full Text :
- https://doi.org/10.1038/s41586-024-07379-z