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

GSE268000 Mus musculus (mouse) RNA-seq (gene expression) 12 samples Submitted 2024/07/12 Platform GPL34290
At a glance

RNA-seq (gene expression) · mouse · 12 samples

What it is
RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism
Mus musculus (mouse)
Samples
12 samples: 3 × KP-1 Cells, DMSO Treatment for 48 hours, vs 3 × KP-1 Cells, HRS4642 Treatment for 48 hours, vs 3 × KP-1 Cells, Carfilzomib Treatment for 48 hours, vs 3 × KP-1 Cells, HRS4642 and Carfilzomib Treatment for 48 hours,Groups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper
Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancerCancer cell · 2024
Summary (written by the submitters)
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.
Read the full summary ↓
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.
Published in
Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer
Zhou C, Li C, Luo L et al. · Cancer cell 2024 · PMID 38942026 · doi:10.1016/j.ccell.2024.06.001
This dataset
Open GSE268000 in finder → Find more mouse RNA-seq datasets →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE268000_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1114010 and SRA study SRP509147. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 38942026) ↗
Study design
3 × KP-1 Cells, DMSO Treatment for 48 hours, vs 3 × KP-1 Cells, HRS4642 Treatment for 48 hours, vs 3 × KP-1 Cells, Carfilzomib Treatment for 48 hours, vs 3 × KP-1 Cells, HRS4642 and Carfilzomib Treatment for 48 hours,

Supports a between-group comparison across 12 samples.

How we read this: 4 replicated groups read from 12 sample titles; they account for 12 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study
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