Strategies to target energy metabolism in consensus molecular subtype 3 along with Kirsten rat sarcoma viral oncogene homolog mutations for colorectal cancer therapy

Abstract Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide and 30% of patients with CRC experience metastasis. Patients with metastatic colorectal cancer (mCRC) have a 5-year overall survival rate of <10%. V-raf murine sarcoma viral oncogene homolog B1 (BRAF) and V-Ki-ras2 Kirsten ratsarcoma viral oncogene homolog (KRAS) mutations are mostly studied in mCRC, as clinical trials found that first-line chemotherapy with anti-epidermal growth factor receptor agent confers limited efficacy for mCRC. Treatment decisions for early-stage mCRC do not consider BRAF or KRAS mutations, given the dramatically poor prognosis conferred by these mutations in clinical trials. Thus, it is necessary to identify patients with mCRC harboring BRAF or KRAS mutations to formulate rational therapeutic strategies to improve prognosis and survival. BRAF and KRAS mutations occur in ∼10% and ∼44% of patients with mCRC, respectively. Although the survival rate of patients with mCRC has improved in recent years, the response and prognosis of patients with the aforementioned mutations are still poor. There is a substantial unmet need for prospective personalized therapies for patients with BRAF- or KRAS-mutant mCRC. In this review, we focus on BRAF and KRAS mutations to understand the mechanisms underlying resistance and improving the response rate, outcomes, and prognosis of patients with mCRC bearing these mutations and to discuss prospective personalized therapies for BRAF- and KRAS-mutant mCRC.

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Human Colorectal Cancer from the Perspective of Mouse Models

Genes ◽

10.3390/genes10100788 ◽

2019 ◽

Vol 10 (10) ◽

pp. 788 ◽

Cited By ~ 4

Author(s):

Monika Stastna ◽

Lucie Janeckova ◽

Dusan Hrckulak ◽

Vitezslav Kriz ◽

Vladimir Korinek

Keyword(s):

Colorectal Cancer ◽

Growth Factor ◽

Mouse Models ◽

Intracellular Signaling ◽

Transforming Growth Factor ◽

Molecular Subtype ◽

Transforming Growth Factor Β ◽

Dna Mismatch ◽

Individual Mouse ◽

Consensus Molecular Subtype

Colorectal cancer (CRC) is a heterogeneous disease that includes both hereditary and sporadic types of tumors. Tumor initiation and growth is driven by mutational or epigenetic changes that alter the function or expression of multiple genes. The genes predominantly encode components of various intracellular signaling cascades. In this review, we present mouse intestinal cancer models that include alterations in the Wnt, Hippo, p53, epidermal growth factor (EGF), and transforming growth factor β (TGFβ) pathways; models of impaired DNA mismatch repair and chemically induced tumorigenesis are included. Based on their molecular biology characteristics and mutational and epigenetic status, human colorectal carcinomas were divided into four so-called consensus molecular subtype (CMS) groups. It was shown subsequently that the CMS classification system could be applied to various cell lines derived from intestinal tumors and tumor-derived organoids. Although the CMS system facilitates characterization of human CRC, individual mouse models were not assigned to some of the CMS groups. Thus, we also indicate the possible assignment of described animal models to the CMS group. This might be helpful for selection of a suitable mouse strain to study a particular type of CRC.

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Metastatic Colorectal Cancer Treatment Patterns According to Kirsten Rat Sarcoma Viral Oncogene Homolog Genotype in U.S. Community-Based Oncology Practices

Clinical Colorectal Cancer ◽

10.1016/j.clcc.2014.05.001 ◽

2014 ◽

Vol 13 (3) ◽

pp. 178-184 ◽

Cited By ~ 4

Author(s):

Pamela B. Landsman-Blumberg ◽

Gebra Cuyun Carter ◽

Barbara H. Johnson ◽

Robert Sedgley ◽

Steven J. Nicol ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Treatment ◽

Metastatic Colorectal Cancer ◽

Treatment Patterns ◽

Community Based ◽

Viral Oncogene ◽

Viral Oncogene Homolog ◽

Colorectal Cancer Treatment

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Stratified analysis reveals chemokine-like factor (CKLF) as a potential prognostic marker in the MSI-immune consensus molecular subtype CMS1 of colorectal cancer

Oncotarget ◽

10.18632/oncotarget.9126 ◽

2016 ◽

Vol 7 (24) ◽

pp. 36632-36644 ◽

Cited By ~ 4

Author(s):

Philip D. Dunne ◽

Paul G. O’Reilly ◽

Helen G. Coleman ◽

Ronan T. Gray ◽

Daniel B. Longley ◽

...

Keyword(s):

Colorectal Cancer ◽

Prognostic Marker ◽

Molecular Subtype ◽

Consensus Molecular Subtype ◽

Stratified Analysis

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Bi-clustering based biological and clinical characterization of colorectal cancer in complementary to CMS classification

10.1101/508275 ◽

2018 ◽

Author(s):

Sha Cao ◽

Wennan Chang ◽

Changlin Wan ◽

Yong Zhang ◽

Jing Zhao ◽

...

Keyword(s):

Colorectal Cancer ◽

Drug Resistance ◽

Large Scale ◽

Molecular Subtype ◽

Resistance Mechanisms ◽

Low Rank ◽

Data Sets ◽

Alternative Drug ◽

Transcriptomics Data ◽

Consensus Molecular Subtype

In light of the marked differences in the intrinsic biological underpinnings and prognostic outcomes among different subtypes, Consensus Molecular Subtype (CMS) classification provides a new taxonomy of colorectal cancer (CRC) solely based on transcriptomics data and has been accepted as a standard rule for CRC stratification. Even though CMS was built on highly cancer relevant features, it suffers from limitations in capturing the promiscuous mechanisms in a clinical setting. There are at least two facts about using transcriptomic data for prognosis prediction: the engagement of genes or pathways that execute the clinical response pathway are highly dynamic and interactive with others; and a predefined patient stratification not only largely decrease the statistical analysis power, but also excludes the fact that clusters of patients that confer similar clinical outcomes may or may not overlap with a pre-defined subgrouping. To enable a flexible and prospective stratified exploration, we here present a novel computational framework based on bi-clustering aiming to identify gene regulatory mechanisms associated with various biological, clinical and drug-resistance features, with full recognition of the transiency of transcriptional regulation and complicacies of patients subgrouping with regards to different biological and clinical settings. Our analysis on multiple large scale CRC transcriptomics data sets using a bi-clustering based formulation suggests that the detected local low rank modules can not only generate new biological understanding coherent to CMS stratification, but also identify predictive markers for prognosis that are general to CRC or CMS dependent, as well as novel alternative drug resistance mechanisms. Our key results include: (1) a comprehensive annotation of the local low rank module landscape of CRC; (2) a mechanistic relationship between different clinical subtypes and outcomes, as well as their characteristic biological underpinnings, visible through a novel consensus map; and (3) a few (novel) resistance mechanisms of Oxaliplatin, 5-Fluorouracil, and the FOLFOX therapy are revealed, some of which are validated on independent datasets.

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Investigation of colorectal cancer in accordance with consensus molecular subtype classification

Annals of Gastroenterological Surgery ◽

10.1002/ags3.12362 ◽

2020 ◽

Vol 4 (5) ◽

pp. 528-539

Author(s):

Hiroshi Sawayama ◽

Yuji Miyamoto ◽

Katsuhiro Ogawa ◽

Naoya Yoshida ◽

Hideo Baba

Keyword(s):

Colorectal Cancer ◽

Molecular Subtype ◽

Subtype Classification ◽

Consensus Molecular Subtype

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A pre-existing population of ZEB2+ quiescent cells with stemness and mesenchymal features dictate chemoresistance in colorectal cancer

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1505-4 ◽

2020 ◽

Vol 39 (1) ◽

Cited By ~ 7

Author(s):

Federica Francescangeli ◽

Paola Contavalli ◽

Maria Laura De Angelis ◽

Silvia Careccia ◽

Michele Signore ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cell ◽

Molecular Subtype ◽

Cancer Prognosis ◽

Mesenchymal Transition ◽

Tumor Xenografts ◽

Dismal Prognosis ◽

Large Patient ◽

Slow Cycling ◽

Consensus Molecular Subtype

Abstract Background Quiescent/slow cycling cells have been identified in several tumors and correlated with therapy resistance. However, the features of chemoresistant populations and the molecular factors linking quiescence to chemoresistance are largely unknown. Methods A population of chemoresistant quiescent/slow cycling cells was isolated through PKH26 staining (which allows to separate cells on the basis of their proliferation rate) from colorectal cancer (CRC) xenografts and subjected to global gene expression and pathway activation analyses. Factors expressed by the quiescent/slow cycling population were analyzed through lentiviral overexpression approaches for their ability to induce a dormant chemoresistant state both in vitro and in mouse xenografts. The correlation between quiescence-associated factors, CRC consensus molecular subtype and cancer prognosis was analyzed in large patient datasets. Results Untreated colorectal tumors contain a population of quiescent/slow cycling cells with stem cell features (quiescent cancer stem cells, QCSCs) characterized by a predetermined mesenchymal-like chemoresistant phenotype. QCSCs expressed increased levels of ZEB2, a transcription factor involved in stem cell plasticity and epithelial-mesenchymal transition (EMT), and of antiapototic factors pCRAF and pASK1. ZEB2 overexpression upregulated pCRAF/pASK1 levels resulting in increased chemoresistance, enrichment of cells with stemness/EMT traits and proliferative slowdown of tumor xenografts. In parallel, chemotherapy treatment of tumor xenografts induced the prevalence of QCSCs with a stemness/EMT phenotype and activation of the ZEB2/pCRAF/pASK1 axis, resulting in a chemotherapy-unresponsive state. In CRC patients, increased ZEB2 levels correlated with worse relapse-free survival and were strongly associated to the consensus molecular subtype 4 (CMS4) characterized by dismal prognosis, decreased proliferative rates and upregulation of EMT genes. Conclusions These results show that chemotherapy-naive tumors contain a cell population characterized by a coordinated program of chemoresistance, quiescence, stemness and EMT. Such population becomes prevalent upon drug treatment and is responsible for chemotherapy resistance, thus representing a key target for more effective therapeutic approaches.

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Risk factors and incidence of colorectal cancer according to major molecular subtypes

JNCI Cancer Spectrum ◽

10.1093/jncics/pkaa089 ◽

2020 ◽

Author(s):

Liang Wang ◽

Xiaosheng He ◽

Tomotaka Ugai ◽

Koichiro Haruki ◽

Chun-Han Lo ◽

...

Keyword(s):

Colorectal Cancer ◽

Risk Factors ◽

Risk Factor ◽

Molecular Subtypes ◽

Cpg Island ◽

Molecular Subtype ◽

Statistical Significance ◽

Dietary Factors ◽

Significant Heterogeneity ◽

Subtype 3

Abstract Background Colorectal cancer (CRC) is a heterogeneous disease that can develop via three major pathways, including the conventional, serrated, and alternate pathways. We aimed to examine whether the risk factor profiles differ according to pathway-related molecular subtypes. Methods We examined the association of 24 risk factors with four CRC molecular subtypes based on a combinatorial status of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), BRAF and KRAS mutations by collecting data from two large US cohorts. We used inverse probability weighted duplication-method Cox proportional hazards regression to evaluate differential associations across subtypes. Results We documented 1,175 CRC cases with molecular subtype data: subtype 1 (n = 498; conventional pathway; non-MSI-high, CIMP-low/negative, BRAF-wildtype, KRAS-wildtype), subtype 2 (n = 138; serrated pathway; any MSI status, CIMP-high, BRAF-mutated, KRAS-wildtype), subtype 3 (n = 367; alternate pathway; non-MSI-high, CIMP-low/negative, BRAF-wildtype, KRAS-mutated), and subtype 4 (n = 172; other marker combinations). Statistically significant heterogeneity in associations with CRC subtypes was found for age, sex, and smoking, with a higher hazard ratio (HR) observed for the subtype 2 (HR per 10 years of age = 2.64, 95% CI = 2.13-3.26; HR for female = 2.65, 95% CI = 1.60-4.39; HR per 20-pack-year of smoking = 1.29, 95% CI = 1.14-1.45) than other CRC subtypes (All P for heterogeneity < 0.005). A stronger association was found for adiposity measures with subtype 1 CRC in men and subtype 3 CRC in women, and for several dietary factors with subtype 1 CRC, although these differences did not achieve statistical significance at α = 0.005 level. Conclusions Risk factor profiles may differ for CRC arising from different molecular pathways.

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