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Colorectal cancer classification based on gene expression is not associated with FOLFIRI response

ABSTRACT: Sadanandam et al. (2013) recently published a study based on the use of microarray data to classify colorectal cancer (CRC) samples. The classification claimed to have strong clinical implications, as reflected in the paper title: “A colorectal cancer classification system that associates cellular phenotype and responses to therapy”. They defined five subtypes: (i) inflammatory; (ii) goblet-like; (iii) enterocyte; (iv) transit-amplifying; and (v) stem-like. Based on drug sensitivity data from 21 patients, they also reported that the so-called stem-like subtype show differential sensitivity to FOLFIRI. This is the key result in their publication, since it implies a direct relation between the subtype and the choice of CRC therapy (i.e. FOLFIRI response). However, our analyses using the same drug sensitivity data and results from additional patients showed that the CRC classification reported by Sadanandam et al. is not predictive of FOLFIRI response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE54483 | GEO | 2014/09/10

SECONDARY ACCESSION(S): PRJNA236612

REPOSITORIES: GEO

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Colorectal cancer classification based on gene expression is not associated with FOLFIRI response

Project description:Sadanandam et al. (2013) recently published a study based on the use of microarray data to classify colorectal cancer (CRC) samples. The classification claimed to have strong clinical implications, as reflected in the paper title: “A colorectal cancer classification system that associates cellular phenotype and responses to therapy”. They defined five subtypes: (i) inflammatory; (ii) goblet-like; (iii) enterocyte; (iv) transit-amplifying; and (v) stem-like. Based on drug sensitivity data from 21 patients, they also reported that the so-called stem-like subtype show differential sensitivity to FOLFIRI. This is the key result in their publication, since it implies a direct relation between the subtype and the choice of CRC therapy (i.e. FOLFIRI response). However, our analyses using the same drug sensitivity data and results from additional patients showed that the CRC classification reported by Sadanandam et al. is not predictive of FOLFIRI response. We used the classification algorithm to obtain CRC subtypes from our samples. Then we tested the subtype-drug response association performing a retrospective study.

2014-09-10 | E-GEOD-54483 | biostudies-arrayexpress

Consensus Molecular Subtype predicts differential vulnerability of colorectal cancer to the survivin suppressant YM155 I

Project description:Tumor heterogeneity is a major challenge to the treatment of colorectal cancer (CRC). Recently, a transcriptome-based classification was developed, segregating CRC into four consensus molecular subtypes (CMS) with distinct biological and clinical characteristics. Here, we applied the CMS classification on CRC cell lines to identify novel subtype-specific drug vulnerabilities. We combined publicly available transcriptome data from multiple resources to assign 159 CRC cell lines to CMS. By integrating results from large scale drug screens, we discovered that CMS1 cancer is highly vulnerable to the survivin suppressor YM155. We confirmed our results using an independent panel of CRC cell lines and demonstrate a 100-fold higher sensitivity of CMS1 lines. This vulnerability was specific to YM155 and not observed for commonly used chemotherapeutic agents. In CMS1 cancer, low concentrations of YM155 induced apoptosis and expression signatures associated with NFkappaB and ER stress mediated apoptosis signaling. Using a genome-wide CRISPR/Cas9 screen, we discovered a novel role of genes involved in LDL-receptor recycling as modulators of YM155 response in CMS1 CRC. Our work shows that combining drug response data with CMS classification in cell lines can reveal specific vulnerabilities and propose YM155 as novel CMS1 specific drug.

2018-07-03 | GSE116529 | GEO

Consensus Molecular Subtype predicts differential vulnerability of colorectal cancer to the survivin suppressant YM155 II

2018-07-03 | GSE116528 | GEO

Gene expression data from 10 untreated human colon cancer cell lines

Project description:Omega-3 polyunsaturated fatty acids are normal constituents of the diet and have an essential role in maintaining important cellular functions. Docosahexaenoic acid (DHA) have demonstrated anticancer activities in several in vitro and in vivo studies, and in some clinical studies. The mechanism by which n-3 PUFAs reduce tumor growth probably involves the inhibition of cell proliferation, induction of cell death, or a combination of both. There are differences in sensitivity towards DHA treatment among colorectal cell lines, although the reason why is unclear. 10 human colorectal cell lines, representing 5 different subtypes of colorectal cancer, were included in gene expression analysis. (Pleae refer to Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S, Ostos LC, Lannon WA, Grotzinger C, Del Rio M, et al. “A colorectal cancer classification system that associates cellular phenotype and responses to therapy”. Nat Med. 2013;19:619-625. doi:10.1038/nm.3175 for details on cancer subtype classifications.) Our aim is to identify different levels of genes and pathways correlating with differences in sensitivity towards DHA between the colorectal cell lines for future classification of patients that could benefit from omega-3 PUFA treatment in addition to conventional treatment.

2018-05-08 | E-MTAB-5750 | biostudies-arrayexpress

Molecular subtypes of metastatic colorectal cancer are predictive of patient response to chemo and targeted therapies (part 2)

Project description:We report that previously described molecular subtypes of colorectal cancer are associated with the response to therapy in patients with metastatic disease. We also identified a patient population with high FOLFIRI sensitivity, as indicated by their 2.7-fold longer overall survival when treated with FOLFIRI, as first-line regimen, instead of FOLFOX. Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer.

2017-08-17 | GSE72969 | GEO

Molecular subtypes of metastatic colorectal cancer are predictive of patient response to chemo and targeted therapies (part 1)

2017-08-17 | GSE72968 | GEO

Identification of SNP candidates associated with chemo-responsiveness in colorectal cancer patients

Project description:Response rates of 118 colorectal cancer patients to regiments were evaluated by histoculture drug response assay. Affymetrix SNP 6.0 chips were used to determine genotypes of the same colorectal cancer patients. SNPs associated with chemosensitivity to treatment regiments were identified by genome-wide association study. AV: avastin (Bevacizumab), ER: Erbitux (Cetuximab), FXA: bevacizumab + FOLFOX, FXE: Cetuximab + FOLFOX , FRA: Bevacizumab + FOLFIRI, FRE: Cetuximab + FOLFIRI; Numbers (0-100) represent responsiveness to the given drug regimens; the larger, the better responsive to given regimens

2011-03-25 | GSE21228 | GEO

YTHDF3 improves translation initiation of mRNAs with N6-methyladenosine methylation at 5’ untranslated region by facilitating eIF2AK2 recruitment in oxaliplatin-resistant colorectal cancer

Project description:Oxaliplatin as a first-line drug frequently causes the chemo-resistance on colorectal cancer (CRC). N6-methyladenosine (m6A) methylation has been largely acknowledged in multiple biological functions. However, the molecular mechanisms underlying the m6A methylation in modulating anticancer drug resistance in CRC are still obscure. In present study, RNA-seq was conducted to investigate the transcriptome of CRC tissues from three patients at different disease stages (CapeOx combined chemotherapy sensitivity and resistance).

2022-02-05 | E-MTAB-11323 | biostudies-arrayexpress

Pharmacoproteomic characterisation of human colon and rectal cancer - CPTAC Full Proteomes

Project description:Most molecular cancer therapies act on protein targets but data on the proteome status of patients and cellular models are only beginning to emerge. Here, we profiled the proteomes of 65 colorectal cancer (CRC) cell lines to a depth of >10,000 proteins using mass spectrometry. Integration with proteomes of 90 CRC patients, as well as transcriptomes of 145 cell lines and 89 patients defined integrated CRC subtypes, highlighting cell lines representative of each tumour subtype. Modelling the responses of 52 CRC cell lines to 577 drugs as a function of proteome profiles enabled predicting drug sensitivity for cell lines and patients. Among many novel associations, MERTK was identified as a predictive marker for resistance towards MEK1/2 inhibitors and immunohistochemistry of 1,000 CRC tumours confirmed MERTK as a prognostic survival marker. We provide the proteomic and pharmacological data to the community to e.g. facilitate the design of innovative prospective clinical trials.

2017-12-13 | PXD005353 | Pride

Pharmacoproteomic characterisation of human colon and rectal cancer - CRC65 Kinobeads

2017-12-12 | PXD005355 | Pride

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