PXD047878

PXD047878 is an original dataset announced via ProteomeXchange.

Title	Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma
Description	Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. 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 (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient-derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.
HostingRepository	PRIDE
AnnounceDate	2024-03-15
AnnouncementXML	Submission_2024-03-15_13:09:43.667.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD047878
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Clint Stalnecker
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-17 16:48:42	ID requested
⏵ 1	2024-03-15 13:09:44	announced

10.1101/2023.12.03.569791;

10.6019/PXD047878;

Wasko UN, Jiang J, Curiel-Garcia A, Wang Y, Lee B, Orlen M, Drizyte-Miller K, Menard M, Dilly J, Sastra SA, Palermo CF, Dalton T, Hasselluhn MC, Decker-Farrell AR, Chang S, Jiang L, Wei X, Yang YC, Helland C, Courtney H, Gindin Y, Zhao R, Kemp SB, Clendenin C, Sor R, Vostrejs W, Amparo AA, Hibshman PS, Rees MG, Ronan MM, Roth JA, Bakir B, Badgley MA, Chabot JA, Kluger MD, Manji GA, Quintana E, Wang Z, Smith JAM, Holderfield M, Wildes D, Aguirre AJ, Der CJ, Vonderheide RH, Stanger BZ, Singh M, Olive KP, Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma. bioRxiv, ():(2023) [pubmed]

ProteomeXchange project tag: Cancer (B/D-HPP), Biology/Disease-Driven Human Proteome Project (B/D-HPP), Human Proteome Project

submitter keyword: RMC-7977, KPC,RAS, PDAC

Channing Der
contact affiliation	Lineberger Comprehensive Cancer Center Department of Pharmacology UNC Chapel Hill Chapel Hill NC USA
contact email	channing_der@med.unc.edu
lab head
Clint Stalnecker
contact affiliation	UNC Chapel Hill
contact email	clints@email.unc.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD047878
     1. Label: PRIDE project
     2. Name: Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma