Molecular subtypes and the evolution of treatment management in metastatic colorectal cancer

Colorectal cancer (CRC) is a heterogeneous disease representing a therapeutic challenge, which is further complicated by the common occurrence of several molecular alterations that confer resistance to standard chemotherapy and targeted agents. Mechanisms of resistance have been identified at multiple levels in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAFV600E, and in the HER2 and MET receptors. These alterations represent oncogenic drivers that may co-exist in the same tumor with other primary and acquired alterations via a clonal selection process. Other molecular alterations include DNA damage repair mechanisms and rare kinase fusions, potentially offering a rationale for new therapeutic strategies. In recent years, genomic analysis has been expanded by a more complex study of epigenomic, transcriptomic, and microenvironment features. The Consensus Molecular Subtype (CMS) classification describes four CRC subtypes with distinct biological characteristics that show prognostic and potential predictive value in the clinical setting. Here, we review the panorama of actionable targets in CRC, and the developments in more recent molecular tests, such as liquid biopsy analysis, which are increasingly offering clinicians a means of ensuring optimal tailored treatments for patients with metastatic CRC according to their evolving molecular profile and treatment history.

Download Full-text

The role of PDGFRA as a therapeutic target in young colorectal cancer patients

Journal of Translational Medicine ◽

10.1186/s12967-021-03088-7 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Tae Won Kim ◽

Hye Kyung Hong ◽

Chung Lee ◽

Sunmin Kim ◽

Woo Yong Lee ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Subtype ◽

Age Groups ◽

Young Patients ◽

Growth Factor Receptor ◽

Predictive Biomarker ◽

Molecular Characteristics ◽

Novel Therapeutic Strategies ◽

Consensus Molecular Subtype

Abstract Background Young patients with colorectal cancer (CRC) exhibit poor prognoses compared to older patients due to the difficulty in early diagnosis and treatment. However, the underlying molecular characteristics are still unclear. Methods We conducted a comprehensive analysis of 49 CRC patients without hereditary CRC using the whole-exome and RNA sequencing with tumor and matched normal samples. A total of 594 TCGA samples and 4 patient-derived cells were utilized for validation. Results Consensus molecular subtype 4 (CMS4) (53.85%) and CMS2 (38.46%) were enriched in the young (≤ 40 years) and old (> 60 years) age groups, respectively. A CMS4-associated gene, platelet-derived growth factor receptor α (PDGFRA), was significantly upregulated in young patients with CRC (FC = 3.21, p = 0.0001) and was negatively correlated with age (p = 0.0001, R = − 0.526). Moreover, PDGFRA showed a positive co-expression with metastasis-related genes in young CRC patients. In vitro validation confirmed that young patient-derived cells (PDCs) showed an enriched expression of PDGFRA compared to old PDCs and a reduced proliferation rate by knockdown of PDGFRA. Furthermore, young CRC patients were more sensitive to regorafenib, a PDGFRA-targeting drug, than old CRC patients. Conclusions Our study suggests that CRC in young patients is associated with CMS4 and PDGFRA. In addition, PDGFRA may serve potential of novel therapeutic strategies and represent a predictive biomarker of response to regorafenib for young CRC patients.

Download Full-text

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.

Download Full-text

Molecular sequencing and gene fusion detection in non-small cell lung cancer (NSCLC) patients: Impact of co-existing alterations.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e23103 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e23103-e23103

Author(s):

Ana Martinez de Castro ◽

Jordi Remon ◽

Susana Cedres Perez ◽

Alejandro Navarro ◽

Alexandre Martinez Marti ◽

...

Keyword(s):

Gene Fusion ◽

Kinase Inhibitors ◽

Molecular Profile ◽

Next Generation ◽

Cox Models ◽

Molecular Alterations ◽

Molecular Tests ◽

Kaplan Meier ◽

Metastatic Sites ◽

Nsclc Patients

e23103 Background: There is a growing need for accurate molecular diagnostics for proper targeted therapeutics selection in NSCLC patients (pts). We assess whether next generation techniques increase the identification of alterations in a prospective cohort of NSCLC pts, and evaluate prognostic value of different molecular alterations. Methods: Next generation sequencing (Amplicon-seq, 60 genes) and NanoString Gene fusion (20 genes) testing were conducted in NSCLC pts treated in a single center from November 2014 to May 2016. Overall survival (OS) according to the molecular profile was analysed by Kaplan-Meier method and Cox models. Results: Molecular tests were performed in 73advanced NSCLC pts.Median age was 54 year, 50% were women. Histology: 73% adenocarcinoma; 7% squamous, 20% others (Neuroendocrine, NOS). Tests were performed in biopsies from metastatic sites in 55% of pts.These techniques identified molecular alterations in 89% of cases: TP53 mutation (mut) 37/73 (51%); KRASmut 21/73 (29%); EGFRmut 11/73 (15%) ; CDKN2mut 7/73 (9%); BRAFmut (pG469R), ERBB2mut and METexon14mut in (1/73) 1.3%, respectively; ALKfusion (fus) 2/73 (2.7%); ROS1fus 1/73 (1.3%) , and RET fus 3/73 (4%). Concomitant mutations were identified in 32% of pts mainly with TP53 (TP53/EGFR: (5/11) 45% and TP53/KRAS: (7/21) 33%). Matched targeted treatment was offered in 17/73 (23%), mostly tyrosine kinase inhibitors (TKI); anti-EGFR in 11/17 (65%) and ALK/ROS TKI in 3/17 (17.5%). Three pts (17.5%) received anti-MET or anti-HER2 TKI. OS in this whole population treated with target therapies (n = 17) was 45.7 months (m) (CI95% 26.8-NA). The KRASmut group had median OS of 10 m (CI95% 7.5-NA), while the remaining population with wild type (WT) for all driver alterations had median OS of 23 m (CI95% 20-NA), (HR 1.71 for KRASmut vs WT pts, p = 0.18). The presence of coexisting TP53mut did not negatively impact on OS in the cohorts with EGFRmut and KRASmut (p > 0.1) in a multivariate model. Conclusions: Combined next generation techniques for molecular profile in NSCLC pts identifies molecular alterations that have clinically relevant impact in survival. Coexisting TP53mut alteration shows no detrimental effect in OS.

Download Full-text

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

Download Full-text

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.

Download Full-text

A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy

Cancers ◽

10.3390/cancers10100355 ◽

2018 ◽

Vol 10 (10) ◽

pp. 355 ◽

Cited By ~ 7

Author(s):

Valerio Gelfo ◽

Martina Mazzeschi ◽

Giada Grilli ◽

Moshit Lindzen ◽

Spartaco Santi ◽

...

Keyword(s):

Monoclonal Antibody ◽

Molecular Subtype ◽

Interleukin 1 ◽

Antibody Therapy ◽

Growth Factor Receptor ◽

Poor Response ◽

Extracellular Region ◽

Epidermal Growth ◽

Consensus Molecular Subtype

Cetuximab (CTX) is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), commonly used to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, objective remissions occur only in a minority of patients and are of short duration, with a population of cells surviving the treatment and eventually enabling CTX resistance. Our previous study on CRC xenopatients associated poor response to CTX with increased abundance of a set of pro-inflammatory cytokines, including the interleukins IL-1A, IL-1B and IL-8. Stemming from these observations, our current work aimed to assess the role of IL-1 pathway activity in CTX resistance. We employed a recombinant decoy TRAP IL-1, a soluble protein combining the human immunoglobulin Fc portion linked to the extracellular region of the IL-1-receptor (IL-1R1), able to sequester IL-1 directly from the medium. We generated stable clones expressing and secreting a functional TRAP IL-1 into the culture medium. Our results show that IL-1R1 inhibition leads to a decreased cell proliferation and a dampened MAPK and AKT axes. Moreover, CRC patients not responding to CTX blockage displayed higher levels of IL-1R1 than responsive subjects, and abundant IL-1R1 is predictive of survival in patient datasets specifically for the consensus molecular subtype 1 (CMS1). We conclude that IL-1R1 abundance may represent a therapeutic marker for patients who become refractory to monoclonal antibody therapy, while inhibition of IL-1R1 by TRAP IL-1 may offer a novel therapeutic strategy.

Download Full-text

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

Download Full-text

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.

Download Full-text

Immune Resistance and EGFR Antagonists in Colorectal Cancer

Cancers ◽

10.3390/cancers11081089 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1089 ◽

Cited By ~ 8

Author(s):

Giordano ◽

Remo ◽

Porras ◽

Pancione

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Therapy Resistance ◽

Cell Interaction ◽

Molecular Alterations ◽

Immune Resistance ◽

Epidermal Growth ◽

Mechanistic Basis

: Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy in patients with RAS wild type metastatic colorectal cancer (mCRC) has revolutionized the treatment of CRC, but with less results than initially envisaged. In recent years, the discovery of multiple pathways leading to the escape from anti-EGFR therapy has revealed an enormous complexity and heterogeneity of human CRC due to the intrinsic genomic instability and immune/cancer cell interaction. Therefore, understanding the mechanistic basis of acquired resistance to targeted therapies represents a major challenge to improve the clinical outcomes of patients with CRC. The latest findings strongly suggest that complex molecular alterations coupled with changes of the immune tumor microenvironment may substantially contribute to the clinical efficacy of EGFR antagonist. In this review, we discuss the most recent findings that contribute to both primary and acquired anti-EGFR therapy resistance. In addition, we analyze how strategies aiming to enhance the favorable effects in the tumor microenvironment may contribute to overcome resistance to EGFR therapies.

Download Full-text