PXD055133-1

PXD055133 is an original dataset announced via ProteomeXchange.

Title	RAS-GTP inhibition overcomes acquired resistance to KRASG12C inhibitors mediated by oncogenic and wildtype RAS activation in NSCLC preclinical models: LUN156 PDX
Description	Small molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C mutant tumors, yet responses tend to be transient due to on-treatment resistance. Recently, a RAS(ON) G12C-selective inhibitor, which binds to the active GTP-bound state of KRAS, was introduced into the clinical settings. We generated cell line and PDX resistant models to KRAS G12C(OFF) and RAS(ON) G12C-selective inhibitors that displayed a variety of resistance mechanisms similar to the ones observed in human studies. Here we interrogated resistance mechanisms using a multi-omics strategy consisting of phosphoproteomics, exome sequencing, and RNA-sequencing then coupled these analyses to functional testing using small molecule screens, CRISPR screens and combination with RAS(ON) inhibitors that have entered clinical trials. We found two models that reactivate RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and showed that tumors driven by these resistance mechanisms are vulnerable to dual inhibition by either RAS(ON) G12C-selective combined with RAS(ON) multi-selective inhibitor. Two models, which lack any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity, were sensitive to RAS-GTP inhibition by RAS(ON) multi-selective inhibitor. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS activity and acquired dependence on cell cycle kinases and proteins associated with DNA damage response. Our work highlights KRASi-resistant states that could potentially be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in carefully tailored combinations. It also identifies resistant tumors that have reduced RAS dependance, thereby necessitating alternative therapeutic strategies. These datasets compare parental LUN156 patient-derived xenograft tumors to those with acquired resistance to the KRAS G12C inhibitors, Adagrasib (AR) and RM-4998 (RR). Data are provided for protein expression (ID), global phosphorylation (IMAC), and tyrosine phosphorylation (pY) as indicated in the filenames.
HostingRepository	PRIDE
AnnounceDate	2025-10-08
AnnouncementXML	Submission_2025-10-08_12:57:58.556.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD055133
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-23 07:03:20	ID requested
⏵ 1	2025-10-08 12:57:59	announced

10.6019/PXD055133;

submitter keyword: Lung Cancer, KRAS G12C, Targeted Therapy, Patient-Derived Xenograft

Eric Haura
contact affiliation	Thoracic Oncology Molecular Medicine Program Moffitt Cancer Center Tampa, FL, USA
contact email	eric.haura@moffitt.org
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD055133
     1. Label: PRIDE project
     2. Name: RAS-GTP inhibition overcomes acquired resistance to KRASG12C inhibitors mediated by oncogenic and wildtype RAS activation in NSCLC preclinical models: LUN156 PDX