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Angiogenesis blockade overcomes acquired KRAS G12D inhibitor resistance driven by KRAS-PI3Kγ interaction [scRNA-Seq]

ABSTRACT: Angiogenesis blockade overcomes acquired KRAS G12D inhibitor resistance driven by KRAS-PI3Kγ interaction [scRNA-Seq]

PROVIDER: PRJNA1228565 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32495424.fastq.gz	Fastqsanger.gz
	SRR32495425.fastq.gz	Fastqsanger.gz
	SRR32495426.fastq.gz	Fastqsanger.gz
	SRR32495427.fastq.gz	Fastqsanger.gz
	SRR32495428.fastq.gz	Fastqsanger.gz

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Angiogenesis blockade overcomes acquired KRAS G12D inhibitor resistance driven by KRAS-PI3Kγ interaction

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

Angiogenesis blockade overcomes acquired KRAS G12D inhibitor resistance driven by KRAS-PI3Kγ interaction [scRNA-Seq]

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Angiogenesis blockade overcomes acquired KRAS G12D inhibitor resistance driven by KRAS-PI3Kγ interaction

Project description:Angiogenesis blockade overcomes acquired KRAS G12D inhibitor resistance driven by KRAS-PI3Kγ interaction

| PRJNA1228152 | ENA

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.

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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.

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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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