Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Jenkins, Laura J.; Luk, Ian Y.; Fairlie, W. Douglas; Lee, Erinna F.; Palmieri, Michelle; Schoffer, Kael L.; Tan, Tao; Ng, Irvin; Vukelic, Natalia; Tran, Sharon; Tse, Janson W.T.; Nightingale, Rebecca; Alam, Zakia; Chionh, Fiona; Iatropoulos, George; Ernst, Matthias; Afshar‐Sterle, Shoukat; Desai, Jayesh; Gibbs, Peter; Sieber, Oliver M.; Dhillon, Amardeep S.; Tebbutt, Niall C.; Mariadason, John M.

doi:10.1158/1535-7163.mct-22-0101

Cited by 8 publications

(8 citation statements)

References 47 publications

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“…While combination BRAF plus EGFR inhibitor treatment improves this to ~ 20%, overall survival is increased by only 4 months. One limitation of MAPK pathway inhibitors in general is that they predominantly induce cytostatic effects, and often fail to induce extensive levels of apoptosis (11,14). To investigate if similar effects occur upon BRAF inhibitor treatment of BRAF V600E CRC cells, we treated ve BRAF V600E CRC cell lines with the BRAF inhibitors vemurafenib or encorafenib.…”

Section: Resultsmentioning

confidence: 99%

“…One limitation of BRAF and MAPK/ERK pathway inhibitors in general is their failure to induce substantial levels of apoptosis in CRC and other tumour cell types (11,14). Notably, this is despite these agents inducing the expression of the pro-apoptotic proteins BIM (15)(16)(17), BMF (17) and PUMA (15,17), and repressing expression of the pro-survival MCL-1 (16, 18).…”

Section: Introductionmentioning

confidence: 99%

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BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAFV600E colorectal cancer

Mariadason

Jenkins

Luk

et al. 2023

Preprint

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Metastatic BRAFV600E colorectal cancer (CRC) carries an extremely poor prognosis and is in urgent need of effective new treatments. While the BRAFV600E inhibitor encorafenib in combination with the EGFR inhibitor cetuximab (Enc+Cet) was recently approved for this indication, overall survival is only increased by 3.6 months and objective responses are observed in only 20% of patients. We have found that a limitation of Enc+Cet treatment is the failure to efficiently induce apoptosis in BRAFV600E CRCs, despite inducing expression of the pro-apoptotic protein BIM and repressing expression of the pro-survival protein MCL-1. Here, we show that BRAFV600E CRCs express high basal levels of the pro-survival proteins MCL-1 and BCL-XL, and that combining encorafenib with a BCL-XL inhibitor significantly enhances apoptosis in BRAFV600E CRC cell lines. This effect was directly dependent on the induction of BIM as BIM deletion markedly attenuated BRAF plus BCL-XL inhibitor-induced apoptosis. As thrombocytopenia is an established on-target toxicity of BCL-XL inhibition, we also examined the effect of combining encorafenib with the BCL-XL targeting PROTAC DT2216, and the novel BCL-2/BCL-XL inhibitor dendrimer conjugate AZD0466. Combining encorafenib with DT2216 significantly increased the induction of apoptosis in vitro, while combining encorafenib with AZD0466 was well tolerated in mice and further reduced growth of BRAFV600E CRC xenografts compared to either agent alone. Collectively, these findings demonstrate that combined BRAF and BCL-XL inhibition significantly enhances apoptosis in pre-clinical models of BRAFV600E CRC and is a combination regimen worthy of clinical investigation to improve outcomes for these patients.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAFV600E colorectal cancer

Mariadason

Jenkins

Luk

et al. 2023

Preprint

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“…In addition, a number of studies have shown that a combination of HDAC [valproic acid (VPA), panobinostat, vorinostat, mocetinostat, and entinostat] inhibitors with RAS inhibitors (trametinib and vemurafenib) can significantly block the growth cycle of tumor cells and inhibit the expression of apoptotic proteins, Aurora A oncogene transcription, and RAS-RAF-MEK-ERK and PI3K/AKT signaling pathways, showing a strong synergistic effect. 51,52 For this reason, it may be an effective way to overcome the deficiencies in the existing RAS inhibitors and increase the scope of application of HDAC inhibitors by taking the main pharmacophore in RAS inhibitors or RAS downstream signaling pathway interfering agents as the cap-based group of HDAC inhibitors and synthesizing dualtarget RAS/HDAC inhibitors or HDAC inhibitors that can interfere with the downstream signaling pathways involved in the regulation of RAS via introducing different zinc-ionbinding motifs in their strictures. Rigosertib, a benzyl styrene sulfone compound, was initially considered a non-ATP competitor inhibitor for the master mitotic kinase Polo-like kinase (PLK1).…”

Section: ■ Introductionmentioning

confidence: 99%

Multitargeting HDAC Inhibitors Containing a RAS/RAF Protein Interfering Unit

Wang,

Zhang,

et al. 2024

J. Med. Chem.

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In this work, a series of multitargeting histone deacetylase (HDAC) inhibitors capable of regulating the signal transduction between RAS protein and downstream effectors were obtained by introducing a zinc-ion-binding group into the framework of rigosertib via different linkers. Among them, two representative compounds, XSJ-7 and XSJ-10, not only showed stronger antiproliferative activity against many types of cancer cells including solid tumor cells but also presented more potent inhibition on different subtypes of HDAC than suberoylanilide hydroxamic acid (SAHA). Significantly, XSJ-10 presented moderate pharmacokinetic behaviors and showed stronger antitumor activity than oxaliplatin, SAHA, and rigosertib in the HT-29 xenograft mouse models without significant systemic toxicity. Research on the anticancer mechanism of XSJ-10 revealed that it can effectively induce the apoptosis of cancer cells and suppress the tumor by strongly inhibiting the RAS-RAF-MEK-ERK signaling pathway and the acetylation level of HDAC3.

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“…Among the myriad cellular pathways implicated in colorectal cancer, the RAS/MAP kinase pathway emerges as a linchpin, wielding substantial in uence over cellular processes crucial to cancer development. This signaling cascade, encompassing the RAS family of proteins and the mitogenactivated protein kinase (MAPK) pathway, is renowned for its regulatory prowess in cell proliferation, survival, and differentiation (3). MicroRNAs (miRNAs), small non-coding RNA molecules, have emerged as signi cant orchestrators in the intricate dance of cellular pathways, particularly impacting the RAS/MAP kinase pathway in colorectal cancer.…”

Section: Introductionmentioning

confidence: 99%

Deciphering the Regulatory Symphony: MicroRNA Orchestration of the RAS/MAPK Signaling Pathway and its Interplay across Cellular Networks in Colorectal Cancer Tumorigenesis

Pasdar,

Farzadifar,

Abidi

et al. 2024

Preprint

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The RAS/MAP kinase pathway, pivotal in cancer development, intertwines with microRNAs (miRNAs), shaping CRC's dynamic cellular landscape. This study utilizes a systems biology approach, employing advanced bioinformatics tools to unravel miRNA-mediated regulatory networks in CRC. Investigating miRNA dysregulation, identifying hub genes, and exploring interplay between signaling pathways aim to provide nuanced insights into CRC's molecular landscape. Protein-protein network analysis uncovers the interconnected web of miRNA-targeted genes within the RAS/MAPK signaling pathway. Utilizing STRING and Cytoscape, we pinpoint 13 hub proteins orchestrating network dynamics. GO and KEGG enrichment analyses reveal intricate regulatory mechanisms. Cluster analysis unveils 817 clusters, emphasizing CRC significance. Hub gene promoter motif analysis delves into transcriptional regulatory elements governing CRC pathogenesis. A comprehensive list of miRNAs targeting the PI3K pathway in CRC is presented. Protein-protein interaction networks highlight 13 hub proteins, predominantly linked to transcriptional regulation. Enriched pathways, such as the MAPK cascade, underscore their pivotal roles. Cluster analysis reveals CRC's significance, emphasizing involvement in glucose metabolism. Promoter motif analysis uncovers significant motifs targeted by dysregulated miRNAs. Transcription factor motifs reveal biological roles, with implications in signal transduction and cell proliferation. Enrichment in nucleus-based terms and disruption of cell polarity underscore potential implications in cancer development. This integrative study unravels the regulatory intricacies of miRNAs in the RAS/MAPK signaling pathway, shedding light on CRC's molecular landscape. Identification of hub genes, enriched pathways, and regulatory motifs provides valuable insights for diagnostics and therapeutics, offering promising targets for simultaneous inhibition in cancer cell growth.

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Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

Cited by 8 publications

References 47 publications

BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAFV600E colorectal cancer

BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAFV600E colorectal cancer

Multitargeting HDAC Inhibitors Containing a RAS/RAF Protein Interfering Unit

Deciphering the Regulatory Symphony: MicroRNA Orchestration of the RAS/MAPK Signaling Pathway and its Interplay across Cellular Networks in Colorectal Cancer Tumorigenesis

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