PXD063606

PXD063606 is an original dataset announced via ProteomeXchange.

Title	A structure-based modelling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia
Description	Abstract Mutations activating RAS/RAF/MEK/ERK signaling are associated with poor outcome in acute myeloid leukemia (AML), but therapeutic targeting of this pathway is challenging. Here, we employ a structure-based, dynamic RAS pathway model to successfully predict RAF inhibitor (RAFi) combinations which synergistically suppress ERK signaling in RAS-mutant AML. Our in silico models predicted therapeutic synergy of two iterations of conformation-specific RAF inhibitors: Type I½ + Type II and Type I + Type II. Predictions were validated in vitro in AML cell lines and patient samples, with synergy verified by the Loewe Additivity model. Lifirafenib (Type II) + encorafenib (Type I½) was highly synergistic against both NRAS- and KRAS-mutant lines, while synergy of lifirafenib + SB590885 (Type I) was specific to NRAS-mutants. Immunoblotting confirmed that combination efficacy correlated strongly with decreased RAS pathway activation. Leveraging the pharmacokinetic predictions of our in silico model, both combinations were then assessed in a pre-clinical NRAS-mutant AML patient-derived xenograft (PDX) model, showing significantly improved leukemia growth delay and event-free survival compared with single agent approaches. Assessment of leukemia burden in bone marrow and spleen during treatment further showed site-specific efficacy against circulating and spleen-resident blasts for both combinations. In summary, we report that our structure based-modelling approach can effectively identify novel, non-obvious, and well-tolerated RAFi combinations that are highly effective against in vitro and in vivo models, thereby suggesting alternative potential therapeutic strategies for high-risk RAS-mutant AML.
HostingRepository	PRIDE
AnnounceDate	2026-06-24
AnnouncementXML	Submission_2026-06-24_08:48:51.990.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kieran Wynne
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-05-05 08:02:00	ID requested
⏵ 1	2026-06-24 08:48:52	announced

Dataset with its publication pending

submitter keyword: drug combinations, RAS-mutant acute myeloid leukemia.,structure-based modelling

Professor Jonathan Bond
contact affiliation	University College Dublin, School of Medicine, Systems Biology Ireland Belfield Dublin 4. Children’s Health Ireland at Crumlin, Dublin, Ireland.
contact email	jonathan.bond@ucd.ie
lab head
Kieran Wynne
contact affiliation	University College Dublin
contact email	kieran.wynne1@ucd.ie
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD063606
     1. Label: PRIDE project
     2. Name: A structure-based modelling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia