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An Allele Agnostic Mutant KRAS Inhibitor Demonstrates Broad Spectrum Tumour Growth Inhibition in Pancreatic Ductal Adenocarcinoma

ABSTRACT: An Allele Agnostic Mutant KRAS Inhibitor Demonstrates Broad Spectrum Tumour Growth Inhibition in Pancreatic Ductal Adenocarcinoma

PROVIDER: PRJNA1099229 | ENA |

REPOSITORIES: ENA

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An Allele Agnostic Mutant KRAS Inhibitor Demonstrates Broad Spectrum Tumour Growth Inhibition in Pancreatic Ductal Adenocarcinoma

Project description:KRAS is among the most frequently mutated oncogenes in cancer, and for decades, efforts at pharmacological blockade of its function in solid cancers have been unsuccessful. A notable advance in this endeavor is the recent development of small molecule KRAS inhibitors, which enable direct targeting of the mutant oncoprotein. Here, we comprehensively evaluate the pre-clinical efficacy of BI-2493 (henceforth, “panKRASi”), a first-in-class allele agnostic mutant KRAS inhibitor, in pancreatic ductal adenocarcinoma (PDAC). We report effective tumor growth suppression across a broad range of models, including cell lines, organoids, patient-derived xenografts (PDXs), syngeneic orthotopic models, and prolonged survival in genetically engineered mouse models. Overall, transcriptomic, proteomic, and phospho-proteomic profiling of panKRASi-treated models confirms robust Ras pathway inhibition, along with the sustained regulation of crucial hallmarks essential for tumor maintenance. In panKRASi-treated immune-replete models, we observe increased intratumoral CD8+ effector T cells and decreased infiltration of myeloid cells, along with remodeling of the tumor microenvironment (TME). In the long-term, emergence of resistance to panKRASi monotherapy is associated with increased YAP and MYC signaling within tumor cells, and enhanced expression of immune checkpoints within the TME that impede effective T-cell function and changes in cell composition. Our multifaceted approach identifies potential combinatorial approaches for generating sustained responses to panKRASi.

2025-08-21 | GSE263780 | GEO

An Allele Agnostic Mutant KRAS Inhibitor Demonstrates Broad Spectrum Tumour Growth Inhibition in Pancreatic Ductal Adenocarcinoma

Project description:An Allele Agnostic Mutant KRAS Inhibitor Demonstrates Broad Spectrum Tumour Growth Inhibition in Pancreatic Ductal Adenocarcinoma

| PRJNA1098003 | ENA

An Allele Agnostic Mutant KRAS Inhibitor Demonstrates Broad Spectrum Tumour Growth Inhibition in Pancreatic Ductal Adenocarcinoma

Project description:Mutations in KRAS are a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with over 40% of PDAC patients presenting with KRASG12D mutations. The recent development of small molecule inhibitors targeting KRASG12D, has enabled effective targeting of mutant KRAS signaling and suppression of PDAC; however, the contribution of the tumor microenvironment (TME) to the therapeutic efficacy of KRASG12D inhibition and mechanism/s of resistance to KRASG12D suppression remain to be elucidated. Here, we employed spatial transcriptomics to evaluate cancer cell intrinsic and extrinsic responses to KRASG12D inhibition with panKRASi (BI-2493). In panKRASi-treated immune-replete models, we observe increased intratumoral CD8+ effector T cells and decreased infiltration of myeloid cells, along with remodeling of the tumor microenvironment (TME). In addition, both Cxcl9 and Cxcl10 expression were upregulated in KPCYG12D tumors upon panKRASi treatmen. To dissect the involvement of CAF subtypes in the panKRASi response, we utilized a RCTD deconvolution approach to evaluate their abundance, showing no significant differences in the overall CAF subtype population but a visible increase in the myCAFs population under panKRASi treatment. Focus on cancer-intrinsic mechanisms we reported a switch in cellular identity towards the gene expression of classical signatures in panKRASi treated tumors in both canonical Moffit signature and metaprogram-derived signature. In addition, a decrease in cell cycle-related pathways (E2F targets, G2M checkpoints) and EMT signature was reported for panKRASi treated samples combined with a clear switch from glycolysis to oxidative phosphorylation under treatment with a decrease in p53 and TNF⍺ signaling via NFⲕΒ.

2025-08-21 | GSE263536 | GEO

An Allele Agnostic Mutant KRAS Inhibitor Demonstrates Broad Spectrum Tumour Growth Inhibition in Pancreatic Ductal Adenocarcinoma

Project description:The KRAS oncogene triggers complex phosphorylation cascades, including canonical pathways such as RAF/MEK/ERK, PI3K/AKT, and RALGDS/RAL, and their engagement varies depending on the cancer context. Integration of transcriptomic, proteomic, and phosphoproteomic analysis of KRAS mutant cancers has been used to assess new therapeutic combinations, highlighting KRAS mutant cancer heterogeneity. To dissect the complexity of KRAS dependency in PDAC, we employed unbiased proteome and phosphoproteome analysis to inform on the engagement of phosphorylation cascades and define a proteomic profile of orthotopic mouse tumors with a KrasG12D mutation treated with panKRASi (BI-2493). Treatment-specific changes at phospo/proteomic level (7,134 significantly dysregulated proteins and 6,173 dysregulated phosphosites). Specifically, cell cycle regulatory CDKs are the most significantly suppressed kinases following panKRASi treatment, with a strong downregulation of cell cycle regulatory CDKs and ERK1/2. We also identified enrichment in oxidative phosphorylation and metabolic pathways and suppression of G2M checkpoint and E2F targets, coupled with a decline in DNA replication and cell cycle pathways, suggesting impairment in cell cycle progression. Together, these studies revealed robust suppression of Kras activity and cell cycle progression consistent with tumor growth inhibition and Ki67 staining under panKRASi treatment.

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