Targeting KRAS-mutant stomach/colorectal tumors by disrupting the ERK2-p53 complex

Wang, Xiang; Xie, Qing; Ji, Yan; Yang, Jiaxin; Shen, Jiayan; Peng, Fangfei; Zhang, Yongfeng; Jiang, Feng; Kong, Xiangyin; Ma, Wenzhe; Liu, Dandan; Zheng, Leizhen; Chen, Qing; Lang, Jing-Yu

doi:10.1016/j.celrep.2022.111972

Cited by 3 publications

(3 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The interaction of p53 with other components of the mitogenic MAPK/ERK pathway has been described. For instance, Wang et al recently showed that the ERK2-p53 complex diverts p53 from its canonical tumour suppressor role and that the MEKK inhibitor trametinib promotes dissociation of this complex-restoring p53 function, promoting apoptosis in stomach/colorectal tumours [54]. Differently, our results suggest an interplay between an oncogenic form of p53 with oncogenic BRAF that may account for melanoma malignancy, supporting the efficacy of ITF2357 in targeting both oncogenic factors and disrupting their interaction.…”

Section: Oncogenic Braf Interacts With Oncogenic P53 In Melanoma Cellssupporting

confidence: 73%

Oncogenic BRAF and p53 Interplay in Melanoma Cells and the Effects of the HDAC Inhibitor ITF2357 (Givinostat)

Celesia

Franzò

Liberto

et al. 2023

IJMS

View full text Add to dashboard Cite

Oncogenic BRAF mutations have been widely described in melanomas and promote tumour progression and chemoresistance. We previously provided evidence that the HDAC inhibitor ITF2357 (Givinostat) targets oncogenic BRAF in SK-MEL-28 and A375 melanoma cells. Here, we show that oncogenic BRAF localises to the nucleus of these cells, and the compound decreases BRAF levels in both the nuclear and cytosolic compartments. Although mutations in the tumour suppressor p53 gene are not equally frequent in melanomas compared to BRAF, the functional impairment of the p53 pathway may also contribute to melanoma development and aggressiveness. To understand whether oncogenic BRAF and p53 may cooperate, a possible interplay was considered in the two cell lines displaying a different p53 status, being p53 mutated into an oncogenic form in SK-MEL-28 and wild-type in A375 cells. Immunoprecipitation revealed that BRAF seems to preferentially interact with oncogenic p53. Interestingly, ITF2357 not only reduced BRAF levels but also oncogenic p53 levels in SK-MEL-28 cells. ITF2357 also targeted BRAF in A375 cells but not wild-type p53, which increased, most likely favouring apoptosis. Silencing experiments confirmed that the response to ITF2357 in BRAF-mutated cells depends on p53 status, thus providing a rationale for melanoma-targeted therapy.

show abstract

Section: Oncogenic Braf Interacts With Oncogenic P53 In Melanoma Cellssupporting

confidence: 73%

Oncogenic BRAF and p53 Interplay in Melanoma Cells and the Effects of the HDAC Inhibitor ITF2357 (Givinostat)

Celesia

Franzò

Liberto

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…The second-most important mutated gene was BCL2, an anti-apoptosis factor that facilitates cell death during BRAF inhibition ( Sullivan et al 2018 ). Other top mutated genes TP53 ( Wang et al 2023 ), PIK3CA ( Candido et al 2022 ), MAPK1 ( Long et al 2014 ), and more, are known modulators of BRAF activity and dabrafenib response, many of which are under clinical investigation for potential adjuvant targeting strategies in combination with BRAF/MEK inhibition. While these factors had each been recognized in previous (mostly separate) studies, they had yet to be integrated within a single precision oncology model to yield accurate drug response predictions.…”

Section: Resultsmentioning

confidence: 99%

Representing mutations for predicting cancer drug response

Wall,

Ideker

2024

Bioinformatics

View full text Add to dashboard Cite

Motivation Predicting cancer drug response requires a comprehensive assessment of many mutations present across a tumor genome. While current drug response models generally use a binary mutated/unmutated indicator for each gene, not all mutations in a gene are equivalent. Results Here, we construct and evaluate a series of predictive models based on leading methods for quantitative mutation scoring. Such methods include VEST4 and CADD, which score the impact of a mutation on gene function, and CHASMplus, which scores the likelihood a mutation drives cancer. The resulting predictive models capture cellular responses to dabrafenib, which targets BRAF-V600 mutations, whereas models based on binary mutation status do not. Performance improvements generalize to other drugs, extending genetic indications for PIK3CA, ERBB2, EGFR, PARP1, and ABL1 inhibitors. Introducing quantitative mutation features in drug response models increases performance and mechanistic understanding. Availability and implementation Code and example datasets are available at https://github.com/pgwall/qms.

show abstract

“…Traditionally, studies have focused on the effects of individual somatic mutations on tumor phenotypes. However, it has recently been shown that distinct combinations of mutations can result in unique tumor phenotypes that affect the efficacy of specific therapeutics [9][10][11]. For example, mouse intestinal organoids with oncogenic mutations in Kras, Rspo3, Tp53, and Smad4 exhibit a unique resistance to WNT inhibition [9].…”

Section: Introductionmentioning

confidence: 99%

Multi-omic study of genome-edited human colonoid models of colorectal cancer reveal genotype-specific patterns of microRNA regulation

Villanueva

Pan

Rice

et al. 2023

Preprint

View full text Add to dashboard Cite

Combinations of oncogenic mutations drive inter-tumor heterogeneity in colorectal cancer (CRC), which promotes distinct phenotypes and affects therapeutic efficacy. We recently demonstrated that combinations of mutations in mouse small intestinal organoids lead to unique changes in microRNA (miRNA) expression profiles. However, it remains unknown how different mutational backgrounds shape miRNA profiles in the human colon. We leveraged human colonic organoid models, termed colonoids, with gene edits targeting genes commonly mutated in CRC to profile genotype-specific changes in miRNA expression. By small RNA-sequencing we characterized genotype-specific miRNA profiles. We identified one group of miRNAs, including mir-34a-5p and mir-10a-5p, that is strongly downregulated in APC/KRAS/TP53 mutant (AKP-mutant) colonoids. Using chromatin run-on sequencing, we showed that most miRNA alterations in AKP-mutant colonoids are concordant with transcriptional changes. Transcription factor (TF) motif enrichment analysis using transcriptional regulatory elements with increased activity in AKP-mutant colonoids revealed an enrichment of binding sites for multiple oncogenic TFs. Several of these harbor predicted binding sites for mir-10a-5p and/or mir-34a-5p, suggesting these miRNAs may play a role in regulating transcriptional programs in AKP-mutant contexts. Ultimately, our study offers a glimpse into regulatory mechanisms that drive inter-tumor heterogeneity, and we highlight candidate therapeutic targets for the advancement of precision medicine.

show abstract

Targeting KRAS-mutant stomach/colorectal tumors by disrupting the ERK2-p53 complex

Cited by 3 publications

References 67 publications

Oncogenic BRAF and p53 Interplay in Melanoma Cells and the Effects of the HDAC Inhibitor ITF2357 (Givinostat)

Oncogenic BRAF and p53 Interplay in Melanoma Cells and the Effects of the HDAC Inhibitor ITF2357 (Givinostat)

Representing mutations for predicting cancer drug response

Multi-omic study of genome-edited human colonoid models of colorectal cancer reveal genotype-specific patterns of microRNA regulation

Contact Info

Product

Resources

About