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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE263780 | GEO | 2025/08/21

REPOSITORIES: GEO

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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.

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Project description:Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient-derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.

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Stromal evolution of cancer-associated fibroblasts in PDAC GEMMs

Project description:With the advent of cancer immunotherapy, intense investigation has been focused on tumor-infiltrating immune cells. With only a fraction of patients responding to these new therapies, a better understanding of all elements of the tumor microenvironment (TME) that may influence therapeutic outcome is needed. Stromal elements of the TME, chiefly fibroblasts, have emerged as potential contributors to tumor progression and most recently resistance to immunotherapy, but their precise composition and clinical relevance remain incompletely understood. Here we use single-cell transcriptomics to chart the fibroblastic landscape during pancreatic ductal adenocarcinoma (PDAC) progression in animal models, identifying two healthy tissue fibroblast subsets that co-evolve along individual trajectories into four subsets of carcinoma-associated fibroblasts (CAFs).

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

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2021-04-12 | PXD016996 | Pride

Whole exome sequencing of human tumours and cell lines to investigate how ERBB2 and KRAS Alterations mediate response to EGFR inhibitors in early stage Gallbladder Cancer

Project description:Purpose: The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. The development of new and effective treatment has been and continues to be a major public health imperative. Methods: We report mutational and copy number analysis of 44 predominantly early-staged gallbladder tumors and 5-gallbladder cancer cell lines by a combination of directed and whole exome sequencing at an average coverage of 100X and above. Using gallbladder cancer cell lines and xenograft mouse models we performed phospho-proteome array profiling, followed by an in-depth functional characterization. Results: We describe recurrent activating ERBB2 somatic mutation in 6 of 44 gallbladder primary tumors with an overall mutation frequency of 13%, along with KRAS activating mutations in 3 of 44 samples. Consistent with whole exome findings, a phospho-proteomic array profile of 49-tyrosine kinase revealed constitutive phosphorylation of ERBB2 and EGFR that were found to heterodimerize. We demonstrate that treatment with ERBB2-specific, EGFR-specific shRNA or with covalent EGFR family inhibitor BIBW-2992 inhibits transformation, survival, migration, invasion, and tumor forming characteristics of gallbladder cancer cells harboring wild type or KRAS (G13D) but not KRAS (G12V) mutation. Furthermore, we show in vivo reduction in tumor size is paralleled by a reduction in the amounts of phospho-ERK in KRAS (G13D) but not in KRAS (G12V) xenografts, validating the in vitro findings Conclusion: Findings from this study implicate ERBB2 as an important therapeutic target in early stage gallbladder cancer. We also present the first evidence that the presence of KRAS (G12V), but not KRAS (G13D) mutation, may preclude gallbladder cancer patients to respond to anti-EGFR treatment, similar to the clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer.

2018-12-29 | E-MTAB-6619 | biostudies-arrayexpress

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Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer (part 2)

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