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

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

PROVIDER: PRJNA1115528 | ENA |

REPOSITORIES: ENA

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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

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

2024-07-12 | GSE268242 | GEO

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

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

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Expression data comparing KRas(G12D/+);CreT, R26(H1047R/+);KRas(G12D/+);CreT, and MMTV-Neu mouse mammary tumors

Project description:Breast Cancer (BC) has been associated with alterations in signaling through a number of growth factor and hormone regulated pathways. Mouse models for metastatic BC have been developed using oncoproteins that activate PI3K, Stat3 and Ras signaling. To determine the role of each pathway, we analyzed mouse mammary tumor formation when they were activated singly or pairwise. We used microarrays to detect differentially expressed genes in the KRas(G12D/+);CreT and R26(H1047R/+);KRas(G12D/+);CreT tumors Total RNA was extracted from tumors developed by Qiagen RNAeasy kit and hybridized on Affymetrix microarrays.

2015-09-16 | E-GEOD-73073 | biostudies-arrayexpress

RNA sequencing of SW1990 KRAS-G12D or KRAS-G12D/K128R knockin cell lines

Project description:RNA sequencing of SW1990 KRAS-G12D or KRAS-G12D/K128R knockin cell lines

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RNA-SEQ analysis of pancreatic ductal adenocarcinoma tumours in Pdx1-Cre;lsl-KRas[G12D] (KC), Pdx1-Cre;lsl-KRas[G12D];Rosa26-lsl-MYC[DM] (KMC), Pdx1-Cre;lsl-KRas[G12D];Rosa26-lsl-MYC[DM];c-Myc[fl/+] (KMC-Mycfl/+), and Pdx1-Cre;lsl-KRas[G12D];Rosa26-lsl-MYC[DM];Zbtb17[fl/fl] mice (KMC-Miz1fl/fl)

Project description:Activation of endogenously expressed KRas[G12D] in the pancreas of mice gives rise primarily to early stage PanIN lesions, however such lesions can occasionally progress to end-stage ductal adenocarcinoma (PDAC). Progression of KRas[G12D]- initiated lesions to PDAC is accelerated by modest expression of MYC from the Rosa26 locus. Deletion of 1 copy of endogenous c-Myc or both copies of endogenous Zbtb17 (aka Miz1), slows progression to PDAC and extends healthful survival of Pdx1-Cre;lsl-KRas[G12D];Rosa26-lsl-MYC[DM] (KMC) mice. Tumours were removed from mice with all 4 genotypes and validated by histological examination prior to RNA-SEQ analysis.

2020-03-16 | E-MTAB-8797 | biostudies-arrayexpress

Expression data comparing KRas(G12D/+);CreT, R26(H1047R/+);KRas(G12D/+);CreT, and MMTV-Neu mouse mammary tumors

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Mutation-specific and common phosphotyrosine signatures of KRAS G12D and G13D alleles

Project description:KRAS is one of the most frequently mutated genes across all cancer subtypes. Two of the most frequent oncogenic KRAS mutations observed in patients result in glycine to aspartic acid substitution at either codon 12 (G12D) or 13 (G13D). Although the biochemical differences between these two predominant mutations are not fully understood, distinct clinical features of the resulting tumors suggest involvement of disparate signaling mechanisms. When we compared the global and phosphotyrosine proteomic profiles of isogenic colorectal cancer cell lines bearing either G12D or G13D KRAS mutation, we observed both shared as well as unique signaling events induced by the two KRAS mutations.

2021-06-09 | PXD009843 | Pride

KRAS WT and G12D overexpression RNA-seq

Project description:KRAS is an important oncogene in cancer. Long noncoding RNAs (lncRNAs) have been characterized to be involved in various types of cancer. In this study, we investigated the functions of KRAS-responsive lncRNAs in cancer. We perfomed the RNA-seq to examine the lncRNA expression after overexpession of KRAS WT and G12D in H1299 cells.

2020-12-17 | GSE124627 | GEO

RNA sequencing comparing mouse lung cancer cell lines derived from Kras G12D Trp53 -/- and Kras G12D Trp53 -/- sgMga tumors

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2020-11-17 | GSE161606 | GEO

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