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

Authors :
Wasko UN
Jiang J
Dalton TC
Curiel-Garcia A
Edwards AC
Wang Y
Lee B
Orlen M
Tian S
Stalnecker CA
Drizyte-Miller K
Menard M
Dilly J
Sastra SA
Palermo CF
Hasselluhn MC
Decker-Farrell AR
Chang S
Jiang L
Wei X
Yang YC
Helland C
Courtney H
Gindin Y
Muonio K
Zhao R
Kemp SB
Clendenin C
Sor R
Vostrejs WP
Hibshman PS
Amparo AM
Hennessey C
Rees MG
Ronan MM
Roth JA
Brodbeck J
Tomassoni L
Bakir B
Socci ND
Herring LE
Barker NK
Wang J
Cleary JM
Wolpin BM
Chabot JA
Kluger MD
Manji GA
Tsai KY
Sekulic M
Lagana SM
Califano A
Quintana E
Wang Z
Smith JAM
Holderfield M
Wildes D
Lowe SW
Badgley MA
Aguirre AJ
Vonderheide RH
Stanger BZ
Baslan T
Der CJ
Singh M
Olive KP
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).)

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