Characterization of mechanism of action behind acquired resistance to KRASG12D Inhibition in Pancreatic Ductal Adenocarcinoma
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE298318 | GEO | 2026/05/20
REPOSITORIES: GEO
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 anti-tumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.
2023-06-09 | GSE234449 | GEO
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 and CODEX-based spatial proteomics to evaluate cancer cell intrinsic and extrinsic responses to KRASG12D inhibition with MRTX1133. MRTX1133 treatment was associated with increased CD11c+ cells, T cells, and tumor-restraining fibroblasts within proximity to cancer cells, suggesting that antigen presentation and remodeling of the local microenvironment is associated with an effective response to KRASG12D inhibition. In the context of emergence of MRTX1133 therapy resistance, CDK8, a multiprotein mediator complex associated kinase, was identified as a mediator of resistance in part through induction of downstream CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion. Targeting CDK8 in combination with aCTLA-4 immunotherapy overcomes resistance to small molecule mediated targeted KRASG12D inhibition with prolonged survival of mice with PDAC.
2025-12-02 | GSE269679 | GEO
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 and CODEX-based spatial proteomics to evaluate cancer cell intrinsic and extrinsic responses to KRASG12D inhibition with MRTX1133. MRTX1133 treatment was associated with increased CD11c+ cells, T cells, and tumor-restraining fibroblasts within proximity to cancer cells, suggesting that antigen presentation and remodeling of the local microenvironment is associated with an effective response to KRASG12D inhibition. In the context of emergence of MRTX1133 therapy resistance, CDK8, a multiprotein mediator complex associated kinase, was identified as a mediator of resistance in part through induction of downstream CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion. Targeting CDK8 in combination with aCTLA-4 immunotherapy overcomes resistance to small molecule mediated targeted KRASG12D inhibition with prolonged survival of mice with PDAC.
2025-12-02 | GSE269680 | GEO
Project description:Treatment of pancreatic ductal carcinomas (PDACs) has been advanced by the development of KRAS mutant inhibitors. Despite this progress, PDACs invariably develop resistance to these agents by mechanisms that largely remain unclear. The MUC1 gene, which encodes an oncogenic MUC1-C protein, is upregulated in PDAC KRAS G12D tumors. We report that treatment of PDAC cells with the selective KRAS G12D MRTX1133 inhibitor is associated with induction of MUC1-C expression. We show that KRAS G12D inhibition activates a MUC1-C/NF-B p65 auto-inductive pathway. Our results further demonstrate that MUC1-C drives resistance to MRTX1133 by activating the inflammatory IFN type I and II pathways. Of clinical relevance, targeting MUC1-C genetically and pharmacologically reverses MRTX1133 resistance and is synergistic in combination with MRTX1133 treatment. In leveraging MRTX1133-induced upregulation of MUC1-C expression, an anti-MUC1-C (M1C) antibody-drug conjugate (ADC) is highly effective against MRTX1133-resistant PDAC KRAS G12D cell lines, patient-derived organoids and PDX tumor xenograft models. These findings demonstrate that MUC1-C confers resistance of PDAC KRAS G12D mutant cells to MRTX1133 and identify MUC1-C as a target for M1C ADC treatment of PDAC patients who are refractory to MRTX1133 treatment.
2025-04-08 | GSE293756 | GEO
Project description:As many as 90% of human pancreatic ductal adenocarcinoma (PDAC) tumors harbor gain-of-function mutations in the KRAS oncogene. Recently, inhibitors of the most common KRAS mutation, KRASG12D, have entered the clinical arena. However, early evidence suggests that as monotherapy, KRASG12D inhibitors such as MRTX1133 at best provide brief periods of disease stabilization. Hence, there is a growing interest in understanding the mechanisms through which tumors acquire resistance to KRAS inhibition. In the present study, we generated in vitro models of MRTX1133 resistance and subjected parental and drug-resistant cell lines to RNA sequencing. This suggested that MRTX1133-resistant tumor cells undergo a global shift toward histone acetylation. Inhibition of the histone acetyltransferase EP300 reversed the drug-resistant phenotype in vitro, which subsequent RNA sequencing experiments determined was associated with the suppression of pro-survival FOSL1 signaling. Accordingly, siFOSL1 reversed the MRTX1133-resistant phenotype with similar effects on pro-survival signaling. Given the lack of clinically useful EP300 or FOSL1 inhibitors, we next explored whether inhibitors of the acetylation scanning BET proteins would be similarly effective. The addition of BET inhibitors re-sensitized several highly resistant cell lines to MRTX1133 and impaired FOSL1-mediated survival signaling in vitro. In murine models of MRTX1133-resistant PDAC, BET inhibition cooperated with MRTX1133 to markedly extend overall survival. As BET inhibitors are currently under clinical testing, the combination of MRTX1133 and BET inhibitors warrants further investigation, particularly in tumors that have developed resistance to KRAS inhibition.
2026-03-23 | GSE294216 | GEO
Project description:KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.
2024-06-17 | GSE269985 | GEO
Project description:KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.
2024-06-17 | GSE269313 | GEO
Project description:The KRAS G12D mutation is a key oncogenic driver in many solid tumors, including pancreatic, gastric, and colorectal cancers. While recent preclinical studies have characterized features associated with innate and acquired KRAS G12D inhibitor resistance, strategies to overcome resistance, especially in the gastrointestinal cancer context, remain underexplored. Here, we generated nine gastrointestinal cancer models of acquired resistance to the KRAS G12D-selective inhibitor MRTX1133. We identified the enrichment of angiogenesis, hypoxia, and epithelial-to-mesenchymal transition (EMT) in an isogenic patient-derived organoid model of acquired resistance by single-cell RNA sequencing. In the nine resistant models, VEGFA expression and VEGFR2 phosphorylation were unanimously increased. Subsequent mechanistic studies revealed that an autocrine VEGFA signaling loop, initiated by an increased interaction between KRAS and PI3Kγ, drives both EMT and RAS independence. Elevated mitochondrial oxidative stress in resistant cells led to CCT2-mediated KRAS stabilization, thereby enhancing PI3Kγ activity. Moreover, we observed that cancer-vascular paracrine signaling both amplified angiogenesis and EMT signatures in cancer cells and promoted endothelial cell proliferation. Significantly, disruption of VEGFA signaling reversed EMT induction and restored sensitivity to MRTX1133. Concordantly, in mouse xenograft models, the combination of anti-VEGFR2 therapy and MRTX1133 rechallenge significantly reduced tumor growth, angiogenesis, and proliferation markers without adverse effects on body weight. These findings identify a critical role for VEGFA signaling in resistance to KRAS G12D inhibition and provide a rationale for combination therapies targeting angiogenesis in gastrointestinal cancers.
2025-03-03 | GSE290526 | GEO
Project description:The KRAS G12D mutation is a key oncogenic driver in many solid tumors, including pancreatic, gastric, and colorectal cancers. While recent preclinical studies have characterized features associated with innate and acquired KRAS G12D inhibitor resistance, strategies to overcome resistance, especially in the gastrointestinal cancer context, remain underexplored. Here, we generated nine gastrointestinal cancer models of acquired resistance to the KRAS G12D-selective inhibitor MRTX1133. We identified the enrichment of angiogenesis, hypoxia, and epithelial-to-mesenchymal transition (EMT) in an isogenic patient-derived organoid model of acquired resistance by single-cell RNA sequencing. In the nine resistant models, VEGFA expression and VEGFR2 phosphorylation were unanimously increased. Subsequent mechanistic studies revealed that an autocrine VEGFA signaling loop, initiated by an increased interaction between KRAS and PI3Kγ, drives both EMT and RAS independence. Elevated mitochondrial oxidative stress in resistant cells led to CCT2-mediated KRAS stabilization, thereby enhancing PI3Kγ activity. Moreover, we observed that cancer-vascular paracrine signaling both amplified angiogenesis and EMT signatures in cancer cells and promoted endothelial cell proliferation. Significantly, disruption of VEGFA signaling reversed EMT induction and restored sensitivity to MRTX1133. Concordantly, in mouse xenograft models, the combination of anti-VEGFR2 therapy and MRTX1133 rechallenge significantly reduced tumor growth, angiogenesis, and proliferation markers without adverse effects on body weight. These findings identify a critical role for VEGFA signaling in resistance to KRAS G12D inhibition and provide a rationale for combination therapies targeting angiogenesis in gastrointestinal cancers.
2025-03-02 | GSE290487 | GEO
Project description:Intra-tumoral heterogeneity in pancreatic ductal adenocarcinoma (PDAC) is characterized by a balance between basal and classical epithelial cancer cell states, with basal dominance associating with chemoresistance and a dismal prognosis. Targeting oncogenic KRAS, the primary driver of pancreatic cancer, shows early promise in clinical trials but efficacy is limited by acquired resistance. Using genetically engineered mouse models and patient-derived xenografts, we find that basal PDAC cells are highly sensitive to KRAS inhibitors. Employing fluorescent and bioluminescent reporter systems, we longitudinally track cell-state dynamics in vivo and reveal a rapid, KRAS inhibitor-induced enrichment of the classical state. Lineage-tracing identifies these enriched classical PDAC cells to be a reservoir for disease relapse. Genetic ablation of the classical cell-state is synergistic with KRAS inhibition, providing a pre-clinical proof-of-concept for this therapeutic strategy. Our findings motivate combining classical-state directed therapies with KRAS inhibitors to deepen responses and counteract resistance in pancreatic cancer.
2024-07-07 | GSE271300 | GEO