Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction

Cancer is a complex collection of distinct genetic diseases united by common hallmarks. Here, we expand upon the classic hallmarks to include the stress phenotypes of tumorigenesis. We describe a conceptual framework of how oncogene and non-oncogene addictions contribute to these hallmarks and how they can be exploited through stress sensitization and stress overload to selectively kill cancer cells. In particular, we present evidence for a large class of non-oncogenes that are essential for cancer cell survival and present attractive drug targets. Finally, we discuss the path ahead to therapeutic discovery and provide theoretical considerations for combining orthogonal cancer therapies.

[1]  F. Couch,et al.  Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers , 2008, Nature.

[2]  A. Sparks,et al.  The Genomic Landscapes of Human Breast and Colorectal Cancers , 2007, Science.

[3]  J. Shay,et al.  In vivo inhibition of lung cancer by GRN163L: a novel human telomerase inhibitor. , 2005, Cancer research.

[4]  Neil J Ganem,et al.  Tetraploidy, aneuploidy and cancer. , 2007, Current opinion in genetics & development.

[5]  Ji Luo,et al.  Cancer Proliferation Gene Discovery Through Functional Genomics , 2008, Science.

[6]  Mark W. Dewhirst,et al.  Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response , 2008, Nature Reviews Cancer.

[7]  Jiri Bartek,et al.  An Oncogene-Induced DNA Damage Model for Cancer Development , 2008, Science.

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

[9]  P. Johnston,et al.  5-Fluorouracil: mechanisms of action and clinical strategies , 2003, Nature Reviews Cancer.

[10]  J. Downward Targeting RAS signalling pathways in cancer therapy , 2003, Nature Reviews Cancer.

[11]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[12]  A. Ullrich,et al.  Targeting polo-like kinase 1 for cancer therapy , 2006, Nature Reviews Cancer.

[13]  Dimitris Kletsas,et al.  Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions , 2005, Nature.

[14]  Eytan Domany,et al.  Relationship of gene expression and chromosomal abnormalities in colorectal cancer. , 2006, Cancer research.

[15]  B. Druker Inhibition of the Bcr-Abl tyrosine kinase as a therapeutic strategy for CML , 2002, Oncogene.

[16]  Y. Pommier Topoisomerase I inhibitors: camptothecins and beyond , 2006, Nature Reviews Cancer.

[17]  S. Lowe,et al.  Tissue-specific and reversible RNA interference in transgenic mice , 2007, Nature Genetics.

[18]  M. Nowak,et al.  Dynamics of Genetic Instability in Sporadic and Familial Colorectal Cancer , 2002, Cancer biology & therapy.

[19]  G. Parmigiani,et al.  Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses , 2008, Science.

[20]  J. Pouysségur,et al.  Hypoxia signalling in cancer and approaches to enforce tumour regression , 2006, Nature.

[21]  Angelika Amon,et al.  Aneuploidy Affects Proliferation and Spontaneous Immortalization in Mammalian Cells , 2008, Science.

[22]  T. Ørntoft,et al.  DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis , 2005, Nature.

[23]  Ross Tubo,et al.  Mesenchymal stem cells within tumour stroma promote breast cancer metastasis , 2007, Nature.

[24]  Irving L. Weissman,et al.  Association of reactive oxygen species levels and radioresistance in cancer stem cells , 2009, Nature.

[25]  S. Simões,et al.  Bcl-2-targeted antisense therapy (Oblimersen sodium): towards clinical reality. , 2006, Reviews on recent clinical trials.

[26]  Bert Vogelstein,et al.  Mutations of mitotic checkpoint genes in human cancers , 1998, Nature.

[27]  C. Nathan,et al.  Production of large amounts of hydrogen peroxide by human tumor cells. , 1991, Cancer research.

[28]  Li Zhu,et al.  Specific Inhibition of Cyclooxygenase 2 Restores Antitumor Reactivity by Altering the Balance of IL-10 and IL-12 Synthesis1 , 2000, The Journal of Immunology.

[29]  David R. Plas,et al.  Growth Factors Can Influence Cell Growth and Survival through Effects on Glucose Metabolism , 2001, Molecular and Cellular Biology.

[30]  J. Moll,et al.  Aurora kinases and their inhibitors: more than one target and one drug. , 2008, Advances in experimental medicine and biology.

[31]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[32]  Z. Siddik,et al.  Cisplatin: mode of cytotoxic action and molecular basis of resistance , 2003, Oncogene.

[33]  E. White,et al.  Autophagy suppresses tumor progression by limiting chromosomal instability. , 2007, Genes & development.

[34]  D. Tenen,et al.  Reversibility of acute B-cell leukaemia induced by BCR–ABL1 , 2000, Nature Genetics.

[35]  Angelika Amon,et al.  Aneuploidy: Cells Losing Their Balance , 2008, Genetics.

[36]  P. Scherle,et al.  Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors , 2006, Nature Reviews Cancer.

[37]  S. Lowe,et al.  Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas , 2011, Nature.

[38]  Kornelia Polyak,et al.  Microenvironmental regulation of cancer development. , 2008, Current opinion in genetics & development.

[39]  Rameen Beroukhim,et al.  Molecular characterization of the tumor microenvironment in breast cancer. , 2004, Cancer cell.

[40]  Sreenath V. Sharma,et al.  Oncogene addiction: setting the stage for molecularly targeted cancer therapy. , 2007, Genes & development.

[41]  C. Der,et al.  Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer , 2007, Oncogene.

[42]  B. Klein,et al.  Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma , 1997, Nature Genetics.

[43]  L. Vassilev,et al.  MDM2 inhibitors for cancer therapy. , 2007, Trends in molecular medicine.

[44]  Kenneth Chu,et al.  Sustained Loss of a Neoplastic Phenotype by Brief Inactivation of MYC , 2002, Science.

[45]  J. Uhm An Integrated Genomic Analysis of Human Glioblastoma Multiforme , 2009 .

[46]  G. Parmigiani,et al.  The Consensus Coding Sequences of Human Breast and Colorectal Cancers , 2006, Science.

[47]  Bing Li,et al.  Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo , 1993, Nature.

[48]  G. Wahl,et al.  A central role for chromosome breakage in gene amplification, deletion formation, and amplicon integration. , 1991, Genes & development.

[49]  W. Hahn,et al.  Modelling the molecular circuitry of cancer , 2002, Nature Reviews Cancer.

[50]  Christian A. Rees,et al.  Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[51]  Alan Ashworth,et al.  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy , 2005, Nature.

[52]  Kenneth J. Hillan,et al.  Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer , 2004, Nature Reviews Drug Discovery.

[53]  D. Ribatti,et al.  Bortezomib as an antitumor agent. , 2006, Current pharmaceutical biotechnology.

[54]  G. Verdine,et al.  The Challenge of Drugging Undruggable Targets in Cancer: Lessons Learned from Targeting BCL-2 Family Members , 2007, Clinical Cancer Research.

[55]  E. White,et al.  Role of Autophagy in Cancer: Management of Metabolic Stress , 2007, Autophagy.

[56]  S. Rafii,et al.  VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche , 2005, Nature.

[57]  M. Carducci,et al.  Differentiation therapy. , 2020, Current opinion in pharmacology.

[58]  Daniela Gabriel,et al.  Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity , 2008, Molecular Cancer Therapeutics.

[59]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[60]  Ru Wei,et al.  The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth , 2008, Nature.

[61]  Thomas Helleday,et al.  Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase , 2007, Nature.

[62]  Dimitris Kletsas,et al.  Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints , 2006, Nature.

[63]  O. Warburg On the origin of cancer cells. , 1956, Science.

[64]  David M Sabatini,et al.  Defining the role of mTOR in cancer. , 2007, Cancer cell.

[65]  John J McGuire,et al.  Anticancer antifolates: current status and future directions. , 2003, Current pharmaceutical design.

[66]  F. Garrido,et al.  MHC antigens and tumor escape from immune surveillance. , 2001, Advances in cancer research.

[67]  Christopher L. McClendon,et al.  Reaching for high-hanging fruit in drug discovery at protein–protein interfaces , 2007, Nature.

[68]  Andras Szasz,et al.  Hyperthermia today: electric energy, a new opportunity in cancer treatment. , 2006, Journal of cancer research and therapeutics.

[69]  J Wade Harper,et al.  The DNA damage response: ten years after. , 2007, Molecular cell.

[70]  S. Shirasawa,et al.  Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. , 1993, Science.

[71]  B. Weaver,et al.  Decoding the links between mitosis, cancer, and chemotherapy: The mitotic checkpoint, adaptation, and cell death. , 2005, Cancer cell.

[72]  Weiping Zou,et al.  Immunosuppressive networks in the tumour environment and their therapeutic relevance , 2005, Nature Reviews Cancer.

[73]  Gerard I. Evan,et al.  Modeling the Therapeutic Efficacy of p53 Restoration in Tumors , 2006, Cell.

[74]  W. Kaelin The Concept of Synthetic Lethality in the Context of Anticancer Therapy , 2005, Nature Reviews Cancer.

[75]  I. Weinstein Addiction to Oncogenes--the Achilles Heal of Cancer , 2002, Science.

[76]  J. Uhm Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2009 .

[77]  Guido Kroemer,et al.  Tumor cell metabolism: cancer's Achilles' heel. , 2008, Cancer cell.

[78]  R. Figlin,et al.  Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[79]  Aaron Bensimon,et al.  Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication , 2006, Nature.

[80]  Donna Niedzwiecki,et al.  Telomerase mRNA-Transfected Dendritic Cells Stimulate Antigen-Specific CD8+ and CD4+ T Cell Responses in Patients with Metastatic Prostate Cancer 1 , 2005, The Journal of Immunology.

[81]  C. Harley,et al.  Telomerase and cancer therapeutics , 2008, Nature Reviews Cancer.

[82]  L. Hartwell,et al.  Cell cycle control and cancer. , 1994, Science.

[83]  Akiko Shimamura,et al.  Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated. , 2007, The Journal of clinical investigation.

[84]  Liming Yang,et al.  A loss-of-function RNA interference screen for molecular targets in cancer , 2006, Nature.

[85]  D. Felsher,et al.  Reversible tumorigenesis by MYC in hematopoietic lineages. , 1999, Molecular cell.

[86]  C. Pál,et al.  Dosage sensitivity and the evolution of gene families in yeast , 2003, Nature.

[87]  V. Ferrans,et al.  Ras Proteins Induce Senescence by Altering the Intracellular Levels of Reactive Oxygen Species* , 1999, The Journal of Biological Chemistry.

[88]  L. Emens,et al.  GV-1001, an injectable telomerase peptide vaccine for the treatment of solid cancers. , 2007, Current opinion in molecular therapeutics.

[89]  L. Chin,et al.  Essential role for oncogenic Ras in tumour maintenance , 1999, Nature.

[90]  Kylie L. Gorringe,et al.  No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas , 2008, Nature Genetics.

[91]  S. Lindquist,et al.  HSP90 and the chaperoning of cancer , 2005, Nature Reviews Cancer.

[92]  B. Zhivotovsky,et al.  Mitochondria in cancer cells: what is so special about them? , 2008, Trends in cell biology.

[93]  Jorge Cortes,et al.  Flying under the radar: the new wave of BCR–ABL inhibitors , 2007, Nature Reviews Drug Discovery.

[94]  L. Gianni,et al.  Targeting TRAIL Agonistic Receptors for Cancer Therapy , 2007, Clinical Cancer Research.

[95]  Daniel A. Haber,et al.  Epidermal growth factor receptor mutations in lung cancer , 2007, Nature Reviews Cancer.

[96]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[97]  P. Sicinski,et al.  Targeting Cyclins and Cyclin-Dependent Kinases in Cancer: Lessons from Mice, Hopes for Therapeutic Applications in Humans , 2006, Cell cycle.

[98]  P. Richardson,et al.  Bortezomib: proteasome inhibition as an effective anticancer therapy. , 2005, Future oncology.

[99]  G. Evan,et al.  Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. , 1999, Molecular cell.

[100]  K. Wiman,et al.  Reactivation of mutant p53: molecular mechanisms and therapeutic potential , 2007, Oncogene.

[101]  M. Huang,et al.  Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. , 2005, Cancer research.

[102]  Maitreya J. Dunham,et al.  Effects of Aneuploidy on Cellular Physiology and Cell Division in Haploid Yeast , 2007, Science.

[103]  M. Mark,et al.  Loss of poly(ADP‐ribose) polymerase‐1 causes increased tumour latency in p53‐deficient mice , 2001, The EMBO journal.

[104]  Kendra S. Burbank,et al.  Genome-wide genetic analysis of polyploidy in yeast , 2006, Nature.

[105]  S. Gruber,et al.  Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway , 2006, Nature Cell Biology.

[106]  Apurva A Desai,et al.  Sorafenib in advanced clear-cell renal-cell carcinoma. , 2007, The New England journal of medicine.

[107]  A. Giaccia,et al.  The human Ha-ras oncogene induces genomic instability in murine fibroblasts within one cell cycle. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[108]  S. Quezada,et al.  Cell intrinsic mechanisms of T‐cell inhibition and application to cancer therapy , 2008, Immunological reviews.

[109]  L. Staudt,et al.  IRF4 addiction in multiple myeloma , 2008, Nature.

[110]  S. Ashwell,et al.  DNA Damage Detection and Repair Pathways—Recent Advances with Inhibitors of Checkpoint Kinases in Cancer Therapy , 2008, Clinical Cancer Research.

[111]  C. Henderson,et al.  Role of WHO. , 1982, Experientia. Supplementum.

[112]  S. Elledge,et al.  Non-Oncogene Addiction and the Stress Phenotype of Cancer Cells , 2007, Cell.

[113]  Grant W. Brown,et al.  Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map , 2007, Nature.

[114]  S. Lindquist,et al.  Heat Shock Factor 1 Is a Powerful Multifaceted Modifier of Carcinogenesis , 2007, Cell.

[115]  S. Stauffer,et al.  Small molecule inhibition of the Bcl-X(L)-BH3 protein-protein interaction: proof-of-concept of an in vivo chemopotentiator ABT-737. , 2007, Current topics in medicinal chemistry.

[116]  Z. Hall Cancer , 1906, The Hospital.

[117]  Sébastien Bonnet,et al.  A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. , 2007, Cancer cell.

[118]  Zhan Xiao,et al.  Selective Chk1 inhibitors differentially sensitize p53‐deficient cancer cells to cancer therapeutics , 2006, International journal of cancer.

[119]  J. Folkman Angiogenesis: an organizing principle for drug discovery? , 2007, Nature reviews. Drug discovery.

[120]  T. Jacks,et al.  Restoration of p53 function leads to tumour regression in vivo , 2007, Nature.

[121]  R. DePinho,et al.  Connecting chromosomes, crisis, and cancer. , 2002, Science.

[122]  R. Deberardinis,et al.  Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis , 2007, Proceedings of the National Academy of Sciences.

[123]  H. Lane,et al.  ERBB receptors and cancer: the complexity of targeted inhibitors , 2005, Nature Reviews Cancer.

[124]  R. Deberardinis,et al.  The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. , 2008, Cell metabolism.

[125]  Stephen J. Elledge,et al.  Profiling Essential Genes in Human Mammary Cells by Multiplex RNAi Screening , 2008, Science.

[126]  A. Joe,et al.  Oncogene addiction. , 2008, Cancer research.

[127]  G. Hutchins,et al.  Nf1-Dependent Tumors Require a Microenvironment Containing Nf1 +/−- and c-kit-Dependent Bone Marrow , 2008, Cell.