Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer Journal Article
| Authors: | Wasko, U. N.; Jiang, J.; Dalton, T. C.; Curiel-Garcia, A.; Edwards, A. C.; Wang, Y.; Lee, B.; Orlen, M.; Tian, S.; Stalnecker, C. A.; Drizyte-Miller, K.; Menard, M.; Dilly, J.; Sastra, S. A.; Palermo, C. F.; Hasselluhn, M. C.; Decker-Farrell, A. R.; Chang, S.; Jiang, L.; Wei, X.; Yang, Y. C.; Helland, C.; Courtney, H.; Gindin, Y.; Muonio, K.; Zhao, R.; Kemp, S. B.; Clendenin, C.; Sor, R.; Vostrejs, W. P.; Hibshman, P. S.; Amparo, A. M.; Hennessey, C.; Rees, M. G.; Ronan, M. M.; Roth, J. A.; Brodbeck, J.; Tomassoni, L.; Bakir, B.; Socci, N. D.; Herring, L. E.; Barker, N. K.; Wang, J.; Cleary, J. M.; Wolpin, B. M.; Chabot, J. A.; Kluger, M. D.; Manji, G. A.; Tsai, K. Y.; Sekulic, M.; Lagana, S. M.; Califano, A.; Quintana, E.; Wang, Z.; Smith, J. A. M.; Holderfield, M.; Wildes, D.; Lowe, S. W.; Badgley, M. A.; Aguirre, A. J.; Vonderheide, R. H.; Stanger, B. Z.; Baslan, T.; Der, C. J.; Singh, M.; Olive, K. P. |
| Article Title: | Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer |
| Abstract: | 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. © The Author(s) 2024. |
| Keywords: | immunohistochemistry; survival; controlled study; protein expression; protein phosphorylation; human cell; overall survival; genetics; sorafenib; monotherapy; nonhuman; antineoplastic agents; pancreas cancer; pancreatic neoplasms; antineoplastic agent; cell proliferation; multiple reaction monitoring; mass spectrometry; quality control; mouse; animal; metabolism; animals; mice; cancer immunotherapy; apoptosis; neoplasm recurrence, local; gene expression; tumor volume; carcinoma, pancreatic ductal; animal experiment; animal model; antineoplastic activity; drug effect; drug screening; pathology; xenograft model antitumor assays; cell line, tumor; inhibitor; cancer mortality; disease model; xenograft; tumor recurrence; pancreas tumor; tumor cell line; western blotting; pancreatectomy; ras protein; real time polymerase chain reaction; high performance liquid chromatography; ras proteins; tumor growth; tumor; drug therapy; disease models, animal; guanosine triphosphate; protein p21; proto-oncogene proteins p21(ras); verapamil; transcriptome; particle size; distal pancreatectomy; disease treatment; inhibition; gastrin; principal component analysis; pancreatic ductal carcinoma; reversed phase high performance liquid chromatography; acetylcysteine; trametinib; vinculin; cancer; humans; human; male; female; article; cell viability assay; ic50; cobimetinib; ec50; ulixertinib; terfenadine |
| Journal Title: | Nature |
| Volume: | 629 |
| Issue: | 8013 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-05-23 |
| Start Page: | 927 |
| End Page: | 936 |
| Language: | English |
| DOI: | 10.1038/s41586-024-07379-z |
| PUBMED: | 38588697 |
| PROVIDER: | scopus |
| PMCID: | PMC11111406 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Erratum issued, see DOI: 10.1038/s41586-024-08084-7 -- Source: Scopus |
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