The evolving role of cancer cell line-based screens to define the impact of cancer genomes on drug response?

Over the last decade we have witnessed the convergence of two powerful experimental designs toward a common goal of defining the molecular subtypes that underpin the likelihood of a cancer patient responding to treatment in the clinic. The first of these ‘experiments’ has been the systematic sequencing of large numbers of cancer genomes through the International Cancer Genome Consortium and The Cancer Genome Atlas. This endeavour is beginning to yield a complete catalogue of the cancer genes that are critical for tumourigenesis and amongst which we will find tomorrow's biomarkers and drug targets. The second ‘experiment’ has been the use of large-scale biological models such as cancer cell lines to correlate mutations in cancer genes with drug sensitivity, such that one could begin to develop rationale clinical trials to begin to test these hypotheses. It is at this intersection of cancer genome sequencing and biological models that there exists the opportunity to completely transform how we stratify cancer patients in the clinic for treatment.

[1]  Angela N. Brooks,et al.  Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing , 2012, Cell.

[2]  A. Hauschild,et al.  Improved survival with vemurafenib in melanoma with BRAF V600E mutation. , 2011, The New England journal of medicine.

[3]  T. Hubbard,et al.  A census of human cancer genes , 2004, Nature Reviews Cancer.

[4]  A. Hauschild,et al.  Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial , 2012, The Lancet.

[5]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[6]  A. Sivachenko,et al.  Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer , 2012, Nature Genetics.

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

[8]  Hans Clevers,et al.  In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration , 2013, Nature.

[9]  Jong-Hyeon Jeong,et al.  Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  A. Sivachenko,et al.  A Landscape of Driver Mutations in Melanoma , 2012, Cell.

[11]  Dirk Schadendorf,et al.  Improved survival with MEK Inhibition in BRAF-mutated melanoma for the METRIC Study Group , 2012 .

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

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

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

[15]  Eric S. Lander,et al.  The genomic complexity of primary human prostate cancer , 2010, Nature.

[16]  Rossella Bertulli,et al.  Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial , 2004, The Lancet.

[17]  Francisco Cervantes,et al.  Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. , 2006, The New England journal of medicine.

[18]  Susan O'Brien,et al.  Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. , 2006, The New England journal of medicine.

[19]  C. Sawyers,et al.  Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. , 2001, The New England journal of medicine.

[20]  T. Mok,et al.  Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. , 2009, The New England journal of medicine.

[21]  A. McKenna,et al.  The Mutational Landscape of Head and Neck Squamous Cell Carcinoma , 2011, Science.

[22]  J. Baselga,et al.  Trastuzumab emtansine for HER2-positive advanced breast cancer. , 2012, The New England journal of medicine.

[23]  L. Sequist,et al.  Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  J. T. Syverton,et al.  STUDIES ON THE PROPAGATION IN VITRO OF POLIOMYELITIS VIRUSES , 1952, The Journal of experimental medicine.

[25]  R. Shoemaker The NCI60 human tumour cell line anticancer drug screen , 2006, Nature Reviews Cancer.

[26]  F. Markowetz,et al.  The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups , 2012, Nature.

[27]  H. Clevers,et al.  Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche , 2009, Nature.

[28]  M. Stratton,et al.  The cancer genome , 2009, Nature.

[29]  Brian H. Dunford-Shore,et al.  Somatic mutations affect key pathways in lung adenocarcinoma , 2008, Nature.

[30]  Trevor J Pugh,et al.  Initial genome sequencing and analysis of multiple myeloma , 2011, Nature.

[31]  K. Cibulskis,et al.  Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer , 2012, Nature Genetics.

[32]  Hans Clevers,et al.  Crypt stem cells as the cells-of-origin of intestinal cancer , 2009, Nature.

[33]  Jeffrey W. Clark,et al.  Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. , 2010, The New England journal of medicine.

[34]  R. Rosenfeld Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[35]  Hans Clevers,et al.  Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. , 2011, Gastroenterology.

[36]  J. Utikal,et al.  Improved survival with MEK inhibition in BRAF-mutated melanoma. , 2012, The New England journal of medicine.