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Anti-tumor Efficacy of HRS-4642 and Its Potential Combination with Proteasome Inhibition in KRAS G12D-mutant Cancer [CRISPR]

ABSTRACT: KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrats robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibits promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR/Cas9 screening, which unveiled the proteasome as a synergistic target. We further observed that the proteasome inhibitor, carfilzomib, prominently improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, especially when combined with carfilzomib, significantly reshapes the tumor microenvironment towards an immune permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.

ORGANISM(S): Mus musculus

PROVIDER: GSE268242 | GEO | 2024/07/12

REPOSITORIES: GEO

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Anti-tumor Efficacy of HRS-4642 and Its Potential Combination with Proteasome Inhibition in KRAS G12D-mutant Cancer

Project description:KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrats robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibits promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR/Cas9 screening, which unveiled the proteasome as a synergistic target. We further observed that the proteasome inhibitor, carfilzomib, prominently improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, especially when combined with carfilzomib, significantly reshapes the tumor microenvironment towards an immune permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.

2024-07-12 | GSE268000 | GEO

Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

Project description:Oncogenic mutations in tumor cells regulate signaling both within tumor cells and heterotypic stromal cells. However, whether oncogenes regulate tumor cell signaling via stromal cells is poorly understood. Here we show that oncogenic KRAS (KRAS-G12D) uniquely regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with phosphoproteomic multiplexing we conducted a multivariate analysis of heterocellular KRAS-G12D signaling in Pancreatic Ductal Adenocarcinoma (PDA) cells. By engaging heterotypic fibroblasts, KRAS-G12D drives unique reciprocal signaling in tumor cells to employ additional kinases and double the number of regulated signaling nodes from cell-autonomous KRAS-G12D. Heterocellular signaling produces a distinct tumor cell phosphoproteome, total proteome, and increase mitochondria capacity via an IGF1R/AXL-AKT axis. Reciprocal KRAS-G12D phenotypes require a heterocellular context and are unreachable by cell-autonomous KRAS-G12D alone. These results demonstrate oncogene signaling should be viewed as a heterocellular process and our existing homocellular perspective underrepresents the extent of oncogene signaling in cancer.

2016-04-19 | PXD003223 | Pride

A pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers [scRNA-seq]

Project description:KRAS is the most frequently mutated oncogene in human cancers, but to date, only KRASG12C inhibitors have been FDA-approved. Small-molecule inhibitors that target other more prevalent KRAS mutations are in urgent clinical need. Here, we report a highly potent pan-KRAS inhibitor, MCB-294, that selectively targets KRAS, but not HRAS or NRAS. Molecular profiling studies show that MCB-294 binds to and inhibits several KRAS mutants, including G12D, G12C, G12V, thereby disabling KRAS oncogenic signaling. MCB-294 is well tolerated in mice and exhibits remarkable therapeutic efficacy against the growth of a comprehensive range of KRAS-driven cancer cell lines, patient-derived organoids, and tumor xenografts and prolongs mouse survival. By employing an MCB-294 derivative as the KRAS binder, we further identify a VHL-based pan-KRAS degrader, MCB-36, that efficiently degrades KRAS in vitro and in vivo through the ubiquitin-proteasome system. Importantly, MCB-294 and MCB-36 not only effectively kill KRASG12C inhibitor-resistant cells, but also reshape the tumor microenvironment by boosting T cell-mediated anti-tumor immunity. Taken together, our findings demonstrate a successful and feasible strategy for targeting pan-KRAS to impair multifaceted features of KRAS-driven cancers.

2024-08-03 | GSE273300 | GEO

A pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers [CD45+ scRNA-seq]

2024-08-03 | GSE273301 | GEO

A pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers [bulk RNA-seq]

2024-07-30 | GSE273116 | GEO

Disruption of STAT3 signaling promotes KRAS induced lung tumorigenesis

Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFÎºB-induced IL-8-expression by sequestering NFÎºB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFÎºB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance WT: Control lung; KRAS: Lung tumors expressing KRAS G12D; KRAS STAT3 KO: Lung tumors expressing KRAS G12D- STAT3 deficient; tumors of four mice pooled per sample

2015-02-05 | E-GEOD-52798 | biostudies-arrayexpress

Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas

Project description:Proteasome inhibitors, such as bortezomib and carfilzomib, have shown efficacy in anti-cancer therapy in hematological diseases but not in solid cancers. Here, we found that liposarcomas (LPS) are susceptible to proteasome inhibition, and identified drugs that synergize with carfilzomib, such as selinexor, an inhibitor of XPO1-mediated nuclear export. Through quantitative nuclear protein profiling and phospho-kinase arrays, we identified potential mode of actions of this combination, including interference with ribosome biogenesis and inhibition of pro-survival kinase PRAS40. Furthermore, by assessing global protein levels changes, FADS2, a key enzyme regulating fatty acids synthesis, was found down-regulated after proteasome inhibition. Interestingly, SC26196, an inhibitor of FADS2, synergized with carfilzomib. Finally, to identify further combinational options, we performed high-throughput drug screening and uncovered novel drug interactions with carfilzomib. For instance, cyclosporin A, a known immunosuppressive agent, enhanced carfilzomib’s efficacy in vitro and in vivo. Altogether, these results demonstrate that carfilzomib and its combinations could be repurposed for LPS clinical management.

2020-09-28 | PXD020906 | Pride

Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas

2020-09-28 | PXD021001 | Pride

Quantitative timecourse analysis of oncogenic KRAS expression impact on the proteme of pancreatic ductal adenocarcinoma cells.

Project description:To reveal the impact of mutant KRAS expression on the proteome of Pancreatic Ductal Adenocarcinoma (PDAC) cells, we carried out a timecourse quantitative proteomic analysis of tumour cells isolated from an inducible mouse model of PDAC (iKras PDAC) (Ying et al., 2012). In this model, oncogenic Kras (G12D) expression can be controlled by administration of doxycycline(Dox). Cells were grown in the absence of Dox for 48 hrs, before being treated with or without Dox for 4, 8, 12, 24, and 36 hrs, followed by total lysis and quantitative proteomics analysis using Tandem Mass Tagging (TMT). A total of 2 biological replicate experiments were analysed, with all samples from each replicate barcoded and pooled together using TMT 10plex labelling kit (Thermo).

2023-02-12 | PXD038440 | Pride

Quantitative analysis of the impact of CX-5461 on the proteome of Pancreatic ductal adenocarcinoma cells.

Project description:To reveal the effect of CX-5461 (a small-molecule inhibitor of ribosome biogenesis)on the proteome of Pancreatic Ductal Adenocarcinoma (PDAC) cells, we carried out two quantitative proteomics analyses, using tumour cells isolated from an inducible mouse model of PDAC (iKras PDAC) (Ying et al., 2012). In this model, oncogenic Kras (G12D) expression can be controlled by administration of doxycycline (Dox). In the first experiment, Tandem Mass Tagging (TMT) was employed for quantitative analysis of mock vs. CX-5461 (100nM) treated iKras cells for 48 hrs, in presence of Dox (Kras on). In the second experiment, TMT was used to quantitatively analyse the proteomics changes induced by Dox removal (48 hrs), in presence or absence of CX-5461. For this purpose, iKras PDAC cells were seeded and grown for 48 hrs with or without Dox, in the background of mock vs. CX-5461 (100nM) co-treatments. TMT labelling was done using the TMT 6plex labelling kit from Thermo Fisher.

2023-02-12 | PXD038439 | Pride

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