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

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 NF??. Overall design: Pancreas tissue from mice treated with vehicle or panKRASi was collected in formalin and processed into paraffin blocks after 14 days of treatment. Two different tumor areas/mice for a total of four mice per group (vehicle/panKRASi) were combined into a TMA of 4x4. 5 um thick sections were generated, stained with H&E, and scanned with an Zeiss Axio Scan.Z1 prior entering the 10x CytAssist pipeline for spatial transcriptomics.