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Targeting CDK4/6 epigenetically impairs DNA damage repair to overcome the resistance to neoadjuvant chemotherapy in locally advanced rectal cancer II

ABSTRACT: Resistance to neoadjuvant chemotherapy is associated tumor recurrence of locally advanced rectal cancer (LARC), which remains an unmet demand to exploit potential therapeutic strategies to improve clinical outcomes. Here we demonstrated that aberrant activation of cell cycle pathways is correlated with resistance to neoadjuvant chemotherapy in LARC. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators with oxaliplatin identified that CDK4/6 inhibitors synergistically enhanced anti-tumor effects of oxaliplatin both intrinsic and acquired chemo-resistant colon cancer cells. Functional studies in both in vitro and in vivo models showed that CDK4/6 inhibitors significantly increased sensitivity to oxaliplatin. Integrative transcriptomic and chromatin profiling analysis revealed that CDK4/6 inhibitors induced DNA repair defects to enhance sensitivity of oxaliplatin through epigenetically suppression of DNA repair related genes. Mechanistically, CDK4/6 inhibition impairs DNA damage repair through a previously unrecognized RB1/TEAD4/HDAC1 co-repressor complex which contributes to the resistance to neoadjuvant chemotherapy in LARC. Together, our work revealed an important role of CDK4/6 pathway in LARC patients with neoadjuvant chemotherapy, suggesting that targeting CDK4/6 could provide a potentially effective treatment strategy for LARC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207521 | GEO | 2024/02/26

REPOSITORIES: GEO

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Targeting CDK4/6 epigenetically impairs DNA damage repair to overcome the resistance to neoadjuvant chemotherapy in locally advanced rectal cancer

Project description:Resistance to neoadjuvant chemotherapy is associated tumor recurrence of locally advanced rectal cancer (LARC), which remains an unmet demand to exploit potential therapeutic strategies to improve clinical outcomes. Here we demonstrated that aberrant activation of cell cycle pathways is correlated with resistance to neoadjuvant chemotherapy in LARC. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators with oxaliplatin identified that CDK4/6 inhibitors synergistically enhanced anti-tumor effects of oxaliplatin both intrinsic and acquired chemo-resistant colon cancer cells. Functional studies in both in vitro and in vivo models showed that CDK4/6 inhibitors significantly increased sensitivity to oxaliplatin. Integrative transcriptomic and chromatin profiling analysis revealed that CDK4/6 inhibitors induced DNA repair defects to enhance sensitivity of oxaliplatin through epigenetically suppression of DNA repair related genes. Mechanistically, CDK4/6 inhibition impairs DNA damage repair through a previously unrecognized RB1/TEAD4/HDAC1 co-repressor complex which contributes to the resistance to neoadjuvant chemotherapy in LARC. Together, our work revealed an important role of CDK4/6 pathway in LARC patients with neoadjuvant chemotherapy, suggesting that targeting CDK4/6 could provide a potentially effective treatment strategy for LARC.

2024-02-26 | GSE205035 | GEO

Activation of the interferon signaling pathway is associated with resistance to CDK4/6 inhibitors and immune checkpoint activation in ER-positive breast cancer [RNA-seq]

Project description:CDK4/6 inhibitors are highly effective against ER+/HER2- breast cancer (BC); however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6 inhibitors may lead to the identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes. Parental BC cells and their endocrine-resistant derivatives (EndoR) were used in this study. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation-resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. We found that parental and EndoR BC lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high Interferon (IFN) signaling and reduced sensitivity to CDK4/6 inhibitors, thus an ‘IFN-Related Palbociclib-Resistance Signature’ (IRPS) was derived. In two neoadjuvant trials of a CDK4/6 inhibitor plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6 inhibition. PalboR derivatives displayed a dramatic activation of IFN/STAT1-signaling compared to their short-term treated or untreated counterparts. In primary ER+/HER2- tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis. Our study demonstrates that aberrant IFN-signaling is associated with intrinsic resistance to CDK4/6 inhibitors. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN-pathway, which warrants additional studies to clarify its involvement in resistance to CDK4/6 inhibitors.

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Genome-wide single nucleotide resolution of oxaliplatin-DNA adduct repair in drug sensitive and resistant colorectal cancer cell lines

Project description:Platinum-based chemotherapies, including oxaliplatin, are a mainstay in solid tumor treatment and induce cell death by forming intrastrand dinucleotide DNA adducts. Despite their common use, they are highly toxic and approximately half of patients have tumors that are either intrinsically resistant, or that develop resistance. Studies suggest that this resistance is mediated by variations in DNA repair levels or net drug influx. We aimed to better define the roles of nucleotide excision repair and DNA damage formation in platinum resistance by profiling DNA damage levels and repair efficiency in a panel of seven oxaliplatin-sensitive and three oxaliplatin-resistant colorectal cancer cell lines. We assayed repair indirectly as toxicity, and directly measured bulky adduct formation and removal from the genome by slot blot, repair capacity by excision assay, and mapped repair events genome-wide at single nucleotide resolution using XR-Seq. Using this comprehensive approach of combining novel methods and in some cases using proxies for oxaliplatin-DNA damage, we found no significant difference in repair efficiency that could explain the relative sensitivity and resistance of our cell lines. In contrast, the overall levels of oxaliplatin-DNA damage were significantly lower in resistant cells, indicating that decreased formation of damage, rather than increased repair of that damage, is a major determinant of oxaliplatin resistance. Analysis of gene expression using our XR-seq data showed upregulation of membrane transport pathways in resistant cells, and these pathways may contribute to resistance. Additional research is needed to characterize factors mitigating cellular DNA damage formation by platinum compounds.

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Neoadjuvant chemoradiation alters biomarkers of anticancer immunotherapy responses in locally advanced rectal cancer

Project description:Neoadjuvant chemoradiation therapy (CRT) is a widely used preoperative treatment strategy for locally advanced rectal cancer (LARC). However, a few studies have evaluated the molecular changes caused by neoadjuvant CRT in these cancer tissues. Here, we aimed to investigate changes in immunotherapy-related immunogenic effects in response to preoperative CRT in LARC. We analyzed 60 pairs of human LARC tissues before and after irradiation from three independent LARC cohorts, including a LARC patient RNA sequencing (RNA-seq) dataset from our cohort and GSE15781 and GSE94104 datasets. Gene ontology analysis showed that preoperative CRT significantly enriched the immune response in LARC tissues. Moreover, gene set enrichment analysis revealed six significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways associated with downregulated genes, including mismatch repair (MMR) genes, in LARC tissues after CRT in all three cohorts. Radiation also induced apoptosis and downregulated various MMR system-related genes in three colorectal cancer cells. One patient with LARC showed a change in microsatellite instability (MSI) status after CRT, as demonstrated by the loss of MMR protein and PCR for MSI. Moreover, CRT significantly increased tumor mutational burden in LARC tissues. CIBERSORT analysis revealed that the proportions of M2 macrophages and CD8 T cells were significantly increased after CRT in both the RNA-seq dataset and GSE94104. Notably, preoperative CRT increased various immune biomarker scores, such as the interferon-γ signature, the cytolytic activity and the immune signature. Taken together, our findings demonstrated that neoadjuvant CRT modulated the immune-related characteristics of LARC, suggesting that neoadjuvant CRT may enhance the responsiveness of LARC to immunotherapy.

2023-05-31 | GSE233517 | GEO

whole-gene transcriptome profiling of Panc-1 which were treated with conditinal meida (CM) from CAFS or CAFR

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SILAC-Based Quantitative Proteomics Identifies Multifactorial Mechanism of Oxaliplatin Resistance in Pancreatic Cancer Cells

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Targeting CDK4/6 epigenetically impairs DNA damage repair to overcome the resistance to neoadjuvant chemotherapy in locally advanced rectal cancer

Project description:Targeting CDK4/6 epigenetically impairs DNA damage repair to overcome the resistance to neoadjuvant chemotherapy in locally advanced rectal cancer

| PRJNA843319 | ENA

Proteomic analysis upon miR195/497 replacement reveals potential chemo sensitizing candidates for colorectal cancer

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Targeting CDK4/6 epigenetically impairs DNA damage repair to overcome the resistance to neoadjuvant chemotherapy in locally advanced rectal cancer II

Project description:Targeting CDK4/6 epigenetically impairs DNA damage repair to overcome the resistance to neoadjuvant chemotherapy in locally advanced rectal cancer II

| PRJNA855960 | ENA

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