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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE263536 | GEO | 2025/08/21

REPOSITORIES: GEO

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Project description:The maintenance of advanced malignancies relies on continued activity of driver oncogenes, although their rate-limiting role is highly context-dependent with respect to tumor types and associated genetic alterations. Oncogenic Kras mutation is the signature event in human pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible KrasG12D-driven p53 mutant PDAC mouse model establishes that advanced PDAC remains strictly dependent on continued KrasG12D expression and that KrasG12D serves a vital role in the control of tumor metabolism, through stimulation of glucose uptake and channeling of glucose intermediates through the hexosamine biosynthesis pathway (HBP) and the pentose phosphate pathway (PPP). Notably, these studies reveal that oncogenic Kras regulates ribose biogenesis. Unlike canonical models of PPP-mediated ribose biogenesis, we demonstrate that oncogenic Kras drives intermediates from enhanced glycolytic flux into the non-oxidative arm of the PPP, thereby decoupling ribose biogenesis from NADPNADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in Kras-driven PDAC. Primary pancreatic tumor lines were established from p48Cre tetO_LKrasG12D ROSA_rtTAL+ p53L+ mice. Five independent tumor lines (iKras1-5) were used for pancreatic injection into nude mice to generate orthotopic tumors. The mice were kept on doxycycline for 2 weeks until obvious tumor formation. Half of the animals were pulled off doxycycline for 24 hours. Tumors with over 75% cellularity were collected for total RNA prepartion. For in vitro expression profiles, the same five tumor lines were cultured in the presence or absence of doxycycline for 24 hours and total cellular RNA was prepared. For control samples, two independent tumor lines from LSL-KrasG12D p53L+ tumors were cultured in the presence or absence of doxycycline for 24 hours and total cellular RNA was prepared.

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

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