The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

The development of molecularly targeted anticancer agents relies on large panels of tumour-specific preclinical models closely recapitulating the molecular heterogeneity observed in patients. Here we describe the mutational and gene expression analyses of 151 colorectal cancer (CRC) cell lines. We find that the whole spectrum of CRC molecular and transcriptional subtypes, previously defined in patients, is represented in this cell line compendium. Transcriptional outlier analysis identifies RAS/BRAF wild-type cells, resistant to EGFR blockade, functionally and pharmacologically addicted to kinase genes including ALK, FGFR2, NTRK1/2 and RET. The same genes are present as expression outliers in CRC patient samples. Genomic rearrangements (translocations) involving the ALK and NTRK1 genes are associated with the overexpression of the corresponding proteins in CRC specimens. The approach described here can be used to pinpoint CRCs with exquisite dependencies to individual kinases for which clinically approved drugs are already available.

[1]  Li Li,et al.  Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non–Small Cell Lung Cancers , 2009, Molecular Cancer Research.

[2]  Armando Santoro,et al.  Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. , 2004, The New England journal of medicine.

[3]  Liam O'Connor,et al.  Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer. , 2014, Cancer research.

[4]  Limin Fu,et al.  FLAME, a novel fuzzy clustering method for the analysis of DNA microarray data , 2007, BMC Bioinformatics.

[5]  A. Chinnaiyan,et al.  Outlier kinase expression by RNA sequencing as targets for precision therapy. , 2013, Cancer discovery.

[6]  M. Santoro,et al.  Ponatinib (AP24534) is a novel potent inhibitor of oncogenic RET mutants associated with thyroid cancer. , 2013, The Journal of clinical endocrinology and metabolism.

[7]  Sabine Tejpar,et al.  Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. , 2010, The Lancet. Oncology.

[8]  Davide Corà,et al.  A molecularly annotated platform of patient-derived xenografts ("xenopatients") identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. , 2011, Cancer discovery.

[9]  J. Mesirov,et al.  GenePattern 2.0 , 2006, Nature Genetics.

[10]  L. Mazzucchelli,et al.  Multi-Determinants Analysis of Molecular Alterations for Predicting Clinical Benefit to EGFR-Targeted Monoclonal Antibodies in Colorectal Cancer , 2009, PloS one.

[11]  Andrea Bertotti,et al.  Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. , 2013, Cancer discovery.

[12]  R. Tibshirani,et al.  Diagnosis of multiple cancer types by shrunken centroids of gene expression , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Lewis C Cantley,et al.  A colorectal cancer classification system that associates cellular phenotype and responses to therapy , 2013, Nature Medicine.

[14]  H. Woo,et al.  Integrative Analysis of Proteomic Signatures, Mutations, and Drug Responsiveness in the NCI 60 Cancer Cell Line Set , 2010, Molecular Cancer Therapeutics.

[15]  T. Hunter,et al.  The Protein Kinase Complement of the Human Genome , 2002, Science.

[16]  Joshua C. Gilbert,et al.  An Interactive Resource to Identify Cancer Genetic and Lineage Dependencies Targeted by Small Molecules , 2013, Cell.

[17]  Lior Pachter,et al.  Sequence Analysis , 2020, Definitions.

[18]  W. Bodmer,et al.  Cancer cell lines for drug discovery and development. , 2014, Cancer research.

[19]  I. Cree,et al.  Heterogeneity of chemosensitivity of colorectal adenocarcinoma determined by a modified ex vivo ATP-tumor chemosensitivity assay (ATP-TCA) , 2003, Anti-cancer drugs.

[20]  Sabine Tejpar,et al.  KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. , 2011, The Lancet. Oncology.

[21]  W. Bodmer,et al.  Direct and immune mediated antibody targeting of ERBB receptors in a colorectal cancer cell-line panel , 2012, Proceedings of the National Academy of Sciences.

[22]  D. Lambrechts,et al.  Somatic Profiling of the Epidermal Growth Factor Receptor Pathway in Tumors from Patients with Advanced Colorectal Cancer Treated with Chemotherapy ± Cetuximab , 2013, Clinical Cancer Research.

[23]  Yujin Hoshida,et al.  Nearest Template Prediction: A Single-Sample-Based Flexible Class Prediction with Confidence Assessment , 2010, PloS one.

[24]  Cole Trapnell,et al.  Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. , 2010, Nature biotechnology.

[25]  Suzie K. Hight,et al.  Immortalized epithelial cells derived from human colon biopsies express stem cell markers and differentiate in vitro. , 2010, Gastroenterology.

[26]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[27]  Sabine Tejpar,et al.  Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer , 2013, The Journal of pathology.

[28]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of human colon and rectal cancer , 2012, Nature.

[29]  Adam A. Margolin,et al.  The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity , 2012, Nature.

[30]  I. Nagtegaal,et al.  KRAS gene amplification in colorectal cancer and impact on response to EGFR‐targeted therapy , 2013, International journal of cancer.

[31]  S. Ramaswamy,et al.  Systematic identification of genomic markers of drug sensitivity in cancer cells , 2012, Nature.

[32]  F. J. Ramos,et al.  Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/pharmacodynamic phase I dose-escalation study. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[33]  K. Zatloukal,et al.  Novel colon cancer cell lines leading to better understanding of the diversity of respective primary cancers , 2002, Oncogene.

[34]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Mira Ayadi,et al.  Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value , 2013, PLoS medicine.

[36]  Fang Fang,et al.  FusionMap: detecting fusion genes from next-generation sequencing data at base-pair resolution , 2011, Bioinform..

[37]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[38]  James D. Brenton,et al.  Ovarian Cancer Cell Line Panel (OCCP): Clinical Importance of In Vitro Morphological Subtypes , 2014, PloS one.

[39]  Andrea Lombardi Borgia,et al.  The TPM3‐NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition , 2014, Molecular oncology.

[40]  Pierre Laurent-Puig,et al.  Mutations in the RAS‐MAPK, PI(3)K (phosphatidylinositol‐3‐OH kinase) signaling network correlate with poor survival in a population‐based series of colon cancers , 2008, International journal of cancer.

[41]  R. Labianca,et al.  Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer. , 2012, Journal of the National Cancer Institute.

[42]  Alan Mackay,et al.  Functional viability profiles of breast cancer. , 2011, Cancer discovery.

[43]  Florian Markowetz,et al.  Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions , 2013, Nature Medicine.

[44]  Andreas Schlicker,et al.  Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition , 2013, International journal of cancer.

[45]  B. Pan,et al.  FGFR2 Is Amplified in the NCI-H716 Colorectal Cancer Cell Line and Is Required for Growth and Survival , 2014, PloS one.

[46]  Jiang Qian,et al.  TiGER: A database for tissue-specific gene expression and regulation , 2008, BMC Bioinformatics.