Targeting the cancer kinome through polypharmacology

Kinase inhibitors are the largest class of new cancer drugs. However, it is already apparent that most tumours can escape from the inhibition of any single kinase. If it is necessary to inhibit multiple kinases, how do we choose which ones? In this Opinion article, we discuss some of the strategies that are currently being used to identify new therapeutic combinations of kinase targets.

[1]  John B. Shoven,et al.  I , Edinburgh Medical and Surgical Journal.

[2]  Michael J. Fry,et al.  Phosphatidylinositol-3-OH kinase direct target of Ras , 1994, Nature.

[3]  Y. Doki,et al.  Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and therapy. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[4]  L. Distlerath,et al.  History and Accomplishments of the Inter-Company Collaboration for Aids Drug Development , 2000 .

[5]  P. Cohen,et al.  Specificity and mechanism of action of some commonly used protein kinase inhibitors. , 2000, The Biochemical journal.

[6]  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.

[7]  K. Kinzler,et al.  Use of isogenic human cancer cells for high-throughput screening and drug discovery , 2001, Nature Biotechnology.

[8]  P. N. Rao,et al.  Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification , 2001, Science.

[9]  R. Bianco,et al.  Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. , 2001, Cancer research.

[10]  G. Bollag,et al.  Discovery of a novel Raf kinase inhibitor. , 2001, Endocrine-related cancer.

[11]  M. Gonen,et al.  Augmentation of apoptosis and tumor regression by flavopiridol in the presence of CPT-11 in Hct116 colon cancer monolayers and xenografts. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[12]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

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

[14]  D. Strumberg,et al.  Results of phase I pharmacokinetic and pharmacodynamic studies of the Raf kinase inhibitor BAY 43-9006 in patients with solid tumors. , 2002, International journal of clinical pharmacology and therapeutics.

[15]  M. Campiglio,et al.  Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[16]  A. Tefferi,et al.  Treatment of hypereosinophilic syndrome with imatinib mesilate , 2002, The Lancet.

[17]  Peter Marynen,et al.  A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. , 2003, The New England journal of medicine.

[18]  Seth M Steinberg,et al.  A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. , 2003, The New England journal of medicine.

[19]  B. Goldman For investigational targeted drugs, combination trials pose challenges. , 2003, Journal of the National Cancer Institute.

[20]  A. D. Van den Abbeele,et al.  Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  D. Hanahan,et al.  Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. , 2003, The Journal of clinical investigation.

[22]  L. Burdine,et al.  Target identification in chemical genetics: the (often) missing link. , 2004, Chemistry & biology.

[23]  Richard L Schilsky,et al.  Cetuximab in the treatment of colorectal cancer. , 2004, Clinical advances in hematology & oncology : H&O.

[24]  Wei Zhang,et al.  A Missense Mutation in KIT Kinase Domain 1 Correlates with Imatinib Resistance in Gastrointestinal Stromal Tumors , 2004, Cancer Research.

[25]  K. Gelmon,et al.  Treatment of HER-2/neu Overexpressing Breast Cancer Xenograft Models with Trastuzumab (Herceptin) and Gefitinib (ZD1839): Drug Combination Effects on Tumor Growth, HER-2/neu and Epidermal Growth Factor Receptor Expression, and Viable Hypoxic Cell Fraction , 2004, Clinical Cancer Research.

[26]  Channing J Der,et al.  Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis? , 2004, Trends in cell biology.

[27]  Angela Greco,et al.  A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. , 2004, Gastroenterology.

[28]  Renato Martins,et al.  Erlotinib in previously treated non-small-cell lung cancer. , 2005, The New England journal of medicine.

[29]  William Pao,et al.  Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Carlo Rago,et al.  Mutant PIK3CA promotes cell growth and invasion of human cancer cells. , 2005, Cancer cell.

[31]  Yan Shi,et al.  Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo , 2005, Molecular Cancer Therapeutics.

[32]  J. Ptak,et al.  Colorectal cancer: Mutations in a signalling pathway , 2005, Nature.

[33]  H. Varmus,et al.  Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain , 2005, PLoS medicine.

[34]  L. Wodicka,et al.  A small molecule–kinase interaction map for clinical kinase inhibitors , 2005, Nature Biotechnology.

[35]  Koji Yoshimoto,et al.  Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. , 2005, The New England journal of medicine.

[36]  H. Varmus,et al.  KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib , 2005, PLoS medicine.

[37]  Kevan M Shokat,et al.  Features of selective kinase inhibitors. , 2005, Chemistry & biology.

[38]  M. Campiglio,et al.  Is the gefitinib plus trastuzumab combination feasible in breast cancer patients? , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[39]  C. Cordon-Cardo,et al.  A Phase I Clinical Trial of the Sequential Combination of Irinotecan Followed by Flavopiridol , 2005, Clinical Cancer Research.

[40]  Robert Gray,et al.  Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. , 2006, The New England journal of medicine.

[41]  John P. Overington,et al.  Can we rationally design promiscuous drugs? , 2006, Current opinion in structural biology.

[42]  S. Fesik,et al.  RNAi-based screening of the human kinome identifies Akt-cooperating kinases: a new approach to designing efficacious multitargeted kinase inhibitors , 2006, Oncogene.

[43]  K. Bhalla,et al.  Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. , 2006, The New England journal of medicine.

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

[45]  M. Berger,et al.  Lapatinib plus capecitabine for HER2-positive advanced breast cancer. , 2006, The New England journal of medicine.

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

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

[48]  Todd R. Golub,et al.  BRAF mutation predicts sensitivity to MEK inhibition , 2006, Nature.

[49]  D. Hicklin,et al.  Synergistic Antitumor Effects of Combined Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor-2 Targeted Therapy , 2006, Clinical Cancer Research.

[50]  William A Weiss,et al.  A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. , 2006, Cancer cell.

[51]  A. Iafrate,et al.  Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling , 2007, Proceedings of the National Academy of Sciences.

[52]  P. Murawa,et al.  Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group , 2023, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  R. Figlin,et al.  Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. , 2007, The New England journal of medicine.

[54]  D. Bergstrom,et al.  MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. , 2007, Blood.

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

[56]  C. Sawyers,et al.  Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency. , 2007, The Journal of clinical investigation.

[57]  P. Cohen,et al.  The selectivity of protein kinase inhibitors: a further update. , 2007, The Biochemical journal.

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

[59]  R. Figlin,et al.  Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[60]  Joon-Oh Park,et al.  MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling , 2007, Science.

[61]  S. Knapp,et al.  A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases , 2007, Proceedings of the National Academy of Sciences.

[62]  C. Hudis Trastuzumab--mechanism of action and use in clinical practice. , 2007, The New England journal of medicine.

[63]  K. Shokat,et al.  Escape from HER family tyrosine kinase inhibitor therapy by the kinase inactive HER3 , 2007, Nature.

[64]  Keith L. Ligon,et al.  Coactivation of Receptor Tyrosine Kinases Affects the Response of Tumor Cells to Targeted Therapies , 2007, Science.

[65]  G. Stamp,et al.  Binding of Ras to Phosphoinositide 3-Kinase p110α Is Required for Ras- Driven Tumorigenesis in Mice , 2007, Cell.

[66]  Optimising strategies for clinical development of combinations of targeted agents , 2007 .

[67]  K. Shokat,et al.  Chemical Genetics: Where Genetics and Pharmacology Meet , 2007, Cell.

[68]  C. Sawyers,et al.  Cancer: Mixing cocktails , 2007, Nature.

[69]  E. Perez,et al.  Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. , 2007, The New England journal of medicine.

[70]  K. Shokat,et al.  A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. , 2007, Cancer research.

[71]  Gavin Harper,et al.  Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. , 2008, Journal of medicinal chemistry.

[72]  Violeta Serra,et al.  Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. , 2008, Cancer research.

[73]  C. Bokemeyer,et al.  Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I. , 2008, Blood.

[74]  G. Tortora,et al.  EGFR antagonists in cancer treatment. , 2008, The New England journal of medicine.

[75]  A. Hopkins Network pharmacology: the next paradigm in drug discovery. , 2008, Nature chemical biology.

[76]  Stephen K Burley,et al.  SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib , 2008, Proceedings of the National Academy of Sciences.

[77]  Ralph Weissleder,et al.  Effective Use of PI3K and MEK Inhibitors to Treat Mutant K-Ras G12D and PIK3CA H1047R Murine Lung Cancers , 2008, Nature Medicine.

[78]  K. Shokat,et al.  Targeted polypharmacology: Discovery of dual inhibitors of tyrosine and phosphoinositide kinases , 2008, Nature chemical biology.

[79]  A. Sweet-Cordero,et al.  Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon , 2008, Nature Genetics.

[80]  G. Sledge,et al.  A Phase I-II Study of Combined Blockade of the ErbB Receptor Network with Trastuzumab and Gefitinib in Patients with HER2 (ErbB2)-Overexpressing Metastatic Breast Cancer , 2008, Clinical Cancer Research.

[81]  R. Motzer,et al.  Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial , 2008, The Lancet.

[82]  Christopher Weier,et al.  Transient potent BCR-ABL inhibition is sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis. , 2008, Cancer cell.

[83]  Dongsheng Tu,et al.  K-ras mutations and benefit from cetuximab in advanced colorectal cancer. , 2008, The New England journal of medicine.

[84]  Mindy I. Davis,et al.  A quantitative analysis of kinase inhibitor selectivity , 2008, Nature Biotechnology.

[85]  M. Grace,et al.  Kinase requirements in human cells: II. Genetic interaction screens identify kinase requirements following HPV16 E7 expression in cancer cells , 2008, Proceedings of the National Academy of Sciences.

[86]  John G Doench,et al.  Kinase requirements in human cells: I. Comparing kinase requirements across various cell types , 2008, Proceedings of the National Academy of Sciences.

[87]  Irini Akritopoulou-Zanze,et al.  Kinase-targeted libraries: the design and synthesis of novel, potent, and selective kinase inhibitors. , 2009, Drug discovery today.

[88]  M. Sliwkowski,et al.  Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. , 2009, Cancer cell.

[89]  Ben S. Wittner,et al.  Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 , 2009, Nature.

[90]  Michael J. Emanuele,et al.  A Genome-wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions with the Ras Oncogene , 2009, Cell.

[91]  Linda Mol,et al.  Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. , 2009, The New England journal of medicine.

[92]  D. Feldser,et al.  Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma , 2009, Nature.

[93]  A. Hauschild,et al.  Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[94]  T. Clackson,et al.  AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. , 2009, Cancer cell.

[95]  W. Sellers,et al.  PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. , 2009, Cancer research.

[96]  Sridhar Ramaswamy,et al.  Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells , 2009, Cell.

[97]  B. Manning Challenges and Opportunities in Defining the Essential Cancer Kinome , 2009, Science Signaling.