Targeting CDK4/6 epigenetically impairs DNA damage repair to overcome the resistance to neoadjuvant chemotherapy in locally advanced rectal cancer
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ABSTRACT:
PROVIDER: PRJNA843319 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19436500_1.fastq.gz | Fastqsanger.gz | |||
| SRR19436500_2.fastq.gz | Fastqsanger.gz | |||
| SRR19436501_1.fastq.gz | Fastqsanger.gz | |||
| SRR19436501_2.fastq.gz | Fastqsanger.gz | |||
| SRR19436502_1.fastq.gz | Fastqsanger.gz |
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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
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 | GSE207521 | GEO
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
Project description:Background: MicroRNAs (miRNAs) are small, non-coding, RNA molecules which regulate numerous cellular processes. Specific miRNA may be abnormally down-regulated or up-regulated in colorectal cancer and have been found associated with prognosis or response to treatments. However, no study has ever addressed their predictive role in rectal cancer. Therefore, we used microarray technology and RT-PCR to profile miRNA expression patterns in patients (pts) with rectal cancer, with the aim to identify a specific M-bM-^@M-^\signatureM-bM-^@M-^] associated with pathological complete response after neoadjuvant chemo-radiotherapy. Methods: 38 pts with locally advanced rectal cancer (cT3-4/N+) were treated with capecitabine-oxaliplatin and pelvic conformal radiotherapy (45 cGy) followed by surgery (after 6-8 weeks). Pathologic response was scored according to the tumor regression grade (TRG) scale. MiRNA expression profile was analysed by microarray on fresh frozen biopsies obtained before treatment start and confirmed by RT-PCR. The correlation between miRNA expression profile and the TRG coded as TRG1 (pathologic Complete Response-pCR) versus TRG >1 (no pCR) was assessed by statistical analysis methods specifically designed for this study. Findings: 14 miRNAs were selected by arrays analysis as differentially expressed in TRG1 pts and 13 were confirmed by RT-PCR. In particular, 11 miRNAs (miR-1183, miR-483-5p, miR-622, miR-125a-3p, miR-1224-5p, miR-188-5p, miR-1471, miR-671-5p, miR-1909*, miR-630 and miR-765) were significantly up-regulated in TRG1 pts, while 2 miRNAs were under -expressed (miR-1274b and miR-720). miR-622 and miR-630 showed 100% sensitivity and specificity in selecting TRG1 cases and were significantly correlated with EGFR (M-OM-^G2=11M-bM-^@M-"793; p= 0M-bM-^@M-"001) and TS expression (M-OM-^G2=10M-bM-^@M-"589; p= 0M-bM-^@M-"001). Interpretation: A set of 13 miRNAs is strongly associated with pathologic complete response and may represent a specific marker of response to chemo-radiotherapy in locally advanced rectal cancer. Experiments were performed on purified RNA from preoperatory biopsies of 38 patients with histological diagnosis of rectal adenocarcinoma invading through the intestinal wall and/or with pelvic lymph node involvement as evaluated by endorectal ultrasonography (uT3-T4 and/or uN+). Patients were treated with neoadjuvant chemo-radiotherapy (capecitabine + oxaliplatin in combination with 45 Gy of pelvic conformal radiotherapy). Patients have been divided in the following two groups: group A those who had obtained a pathologic complete response M-bM-^@M-^S TRG 1, including the patient without detectable disease who refused surgery, group B any pathologic response other than complete.
2012-04-24 | E-GEOD-29298 | biostudies-arrayexpress
Project description:Improving response to neoadjuvant therapy for patients with locally advanced rectal cancer has the potential to improve organ preservation and disease-free survival. Knowing which patients may need therapeutic escalation or de-escalation from standard-of-care treatment remains an area of investigation. We previously reported the primary and secondary endpoints of our single-arm study combining transforming growth factor beta receptor inhibitor, Galunisertib, with neoadjuvant chemoradiation in patients with locally advanced rectal cancer. Here we analyze RNA sequencing data obtained from tissue biopsies at baseline and after 2 weeks of galunisertib. Differences in expression of pathways associated with MYC, inflammation, and epithelial-to-mesenchymal transition were observed between complete responders (CR) and <CR, with galunisertib upregulating MYC pathway expression in CR. Radiosensitivity and TGFβ response scores demonstrated limited ability to predict for response to galunisertib + chemoradiation. Typically treatment resistant consensus molecular subtype 4 (CMS4), characterized by TGFβ expression, was associated with response to galunisertib + chemoradiation. Differences in correlations between RNA based measures of cell composition and immunohistologic quantification of infiltrates and extracted MRI parameters were observed for CIBERSORT, MCPcounter, and Xcell methodologies. Based on these data, we hypothesize that the stromal radioresistant phenotype driven by TGFβ can be overcome by the addition of galunisertib to chemoradiation in rectal cancer.
2026-02-04 | GSE318268 | GEO
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
Project description:Most patients with locally advanced rectal cancer (LARC) present incomplete pathological response (pIR) to neoadjuvant chemoradiotherapy (nCRT). Despite the efforts to predict treatment response using tumor-molecular features, as differentially expressed genes, no molecule has proved to be a strong biomarker. The tumor secretome analysis is a promising strategy for biomarkers identification, which can be assessed using transcriptomic data. Here, we performed transcriptomic-based secretome analysis to select potentially secreted proteins using an in silico approach. The tumor expression profile of 28 LARC biopsies carefully selected and collected before nCRT was compared with normal rectal tissues (NT). The expression profile showed no significant differences between cases with complete (pCR) and incomplete response to nCRT. Genes with increased expression (pCR = 106 and pIR = 357) were used for secretome analysis based on public databases (Vesiclepedia, Human Cancer Secretome Database and Plasma and Proteome Database). Seventeen potentially secreted candidates (pCR=1, pIR=13 and 3 in both groups) were further investigated in two independent datasets (TCGA and GSE68204) confirming their over-expression in LARC. The potential secreted biomarkers were also confirmed as associated with the nCRT response (GSE68204). These putative proteins are candidates to be assessed in liquid biopsies aiming a personalized treatment in LARC patients.
2019-07-01 | GSE123390 | GEO
Project description:The study objective was to find new biomarkers of treatment response and adverse events in patients receiving neoadjuvant therapy for locally advanced rectal cancer. Patients received neoadjuvant chemotherapy (NACT) followed by chemoradiotherapy (CRT) and underwent treatment evaluation four weeks after CRT completion. Radical pelvic surgery was planned 2-4 weeks later. Patients were scored for treatment adverse events, according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, throughout the neoadjuvant treatment course, including at NACT and CRT completion. Treatment response was assessed by histologic ypTN staging and tumor regression grade (TRG) scoring, as well as progression-free survival (time from Inclusion date to Date of local relapse or Date of metastatic disease, whichever came first) recorded for five years after surgery.
2016-04-21 | GSE65622 | GEO
Project description:Unique sub-clones within rectal tumors may harbor mutations which contribute to inter-patient variation in response to neoadjuvant chemoradiotherapy (nCRT). Analysis of the influence of nCRT on the extent and nature of intra-tumoral genetic heterogeneity in rectal cancer may provide insights into mechanisms of resistance. Ten locally advanced rectal cancer patients underwent pre-treatment biopsies. At the time of surgery, tissue from the treated tumor was obtained and analyzed. Pre- and post-treatment specimens were subjected to whole exome and confirmatory deep sequencing for somatic mutations. Copy number variation was assessed using OncoScan SNP arrays. In total, data from 32 pre/post-treatment samples are provided. The provided data include the pre/post tumor samples and the Affymetrix OncoScan SNP arrays.
2019-09-05 | GSE136872 | GEO
Project description:Locally advanced rectal cancer transcriptomic-based secretome analysis according to neoadjuvant chemoradiotherapy response
| PRJNA510936 | ENA