Gastric cancer management: Kinases as a target therapy

The molecular diagnostics revolution has reshaped the practice of oncology by facilitating the identification of genetic, epigenetic and proteomic modifications correlated with cancer, thus delineating ‘oncomaps’ for various cancer types. These advances have enhanced our understanding of gastric cancer, one of the most fatal diseases worldwide, and culminated in the approval of novel molecular therapies such as trastuzumab. Gastric tumours display recurrent aberrations in key kinase oncogenes such as Her2, epidermal growth factor receptor (EGFR), PI3K, mTOR or c‐Met, suggesting that these receptors are amenable to inhibition using specific drug agents. In this review, we examine the mutational landscape of gastric cancer, the use of kinase inhibitors as targeted therapies in gastric tumours and the clinical trials underway for novel inhibitors, highlighting successes, failures and future directions.

[1]  P. Singh,et al.  Evolution of ramucirumab in the treatment of cancer – A review of literature , 2017, Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners.

[2]  J. Ajani,et al.  Global chemotherapy development for gastric cancer , 2017, Gastric Cancer.

[3]  Burak Bilgin,et al.  Targeting the PD-1 pathway: a new hope for gastrointestinal cancers , 2017, Current medical research and opinion.

[4]  M. Apicella,et al.  Targeted therapies for gastric cancer: failures and hopes from clinical trials , 2017, Oncotarget.

[5]  P. Keegan,et al.  U.S. FDA Approval Summary: Nivolumab for Treatment of Unresectable or Metastatic Melanoma Following Progression on Ipilimumab , 2017, Clinical Cancer Research.

[6]  K. Goldberg,et al.  FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma , 2017, Clinical Cancer Research.

[7]  Dániel Deme,et al.  Ramucirumab – egy új gyógyszer az onkológiában , 2016 .

[8]  Ying Cheng,et al.  Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Apatinib in Patients With Chemotherapy-Refractory Advanced or Metastatic Adenocarcinoma of the Stomach or Gastroesophageal Junction. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  A. Tasker,et al.  The Panitumumab EGFR Complex Reveals a Binding Mechanism That Overcomes Cetuximab Induced Resistance , 2016, PloS one.

[10]  Joon-Oh Park,et al.  Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC--A Randomized Phase III Trial. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  J. Ajani,et al.  Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab , 2016, British Journal of Cancer.

[12]  P. Galle,et al.  Sunitinib added to FOLFIRI versus FOLFIRI in patients with chemorefractory advanced adenocarcinoma of the stomach or lower esophagus: a randomized, placebo-controlled phase II AIO trial with serum biomarker program , 2016, BMC Cancer.

[13]  H. Yoon,et al.  The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability vs. PD-L1. , 2016, Journal of gastrointestinal oncology.

[14]  E. Vasile,et al.  Apatinib in Advanced Gastric Cancer: A Doubtful Step Forward , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  G. Darling,et al.  Improving Outcomes in Resectable Gastric Cancer: A Review of Current and Future Strategies. , 2016, Oncology.

[16]  D. Shen,et al.  Efficacy of adoptive cellular therapy in patients with gastric cancer: a meta-analysis. , 2016, Immunotherapy.

[17]  J. Lunceford,et al.  Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. , 2016, The Lancet. Oncology.

[18]  M. Katoh FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review) , 2016, International journal of molecular medicine.

[19]  L. Rajdev,et al.  Current and emerging therapies in unresectable and recurrent gastric cancer. , 2016, World journal of gastroenterology.

[20]  S. Oh,et al.  The Inositide Signaling Pathway As a Target for Treating Gastric Cancer and Colorectal Cancer , 2016, Front. Physiol..

[21]  J. Araya,et al.  The Gene Expression Status of the PI3K/AKT/mTOR Pathway in Gastric Cancer Tissues and Cell Lines , 2016, Pathology & Oncology Research.

[22]  P. Tan,et al.  Translating gastric cancer genomics into targeted therapies. , 2016, Critical reviews in oncology/hematology.

[23]  F. Roviello,et al.  Apatinib: A novel receptor tyrosine kinase inhibitor for the treatment of gastric cancer. , 2016, Cancer letters.

[24]  A. Callegaro,et al.  A non-randomized dose-escalation Phase I trial of a protein-based immunotherapeutic for the treatment of breast cancer patients with HER2-overexpressing tumors , 2016, Breast Cancer Research and Treatment.

[25]  A. Callegaro,et al.  A phase I/II trial of the safety and clinical activity of a HER2-protein based immunotherapeutic for treating women with HER2-positive metastatic breast cancer , 2016, Breast Cancer Research and Treatment.

[26]  A. A. Jácome,et al.  Personalized medicine in gastric cancer: Where are we and where are we going? , 2016, World journal of gastroenterology.

[27]  D. Chia,et al.  Liquid biopsy for detection of actionable oncogenic mutations in human cancers and electric field induced release and measurement liquid biopsy (eLB). , 2016, The Analyst.

[28]  W. Yong,et al.  Strategies and Advancements in Harnessing the Immune System for Gastric Cancer Immunotherapy , 2015, Journal of immunology research.

[29]  F. Roviello,et al.  c-Met targeting in advanced gastric cancer: An open challenge. , 2015, Cancer letters.

[30]  Joon-Oh Park,et al.  Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  Paul Workman,et al.  Drugging PI3K in cancer: refining targets and therapeutic strategies , 2015, Current opinion in pharmacology.

[32]  A. Corvalán,et al.  Molecular classification of gastric cancer: Towards a pathway-driven targeted therapy , 2015, Oncotarget.

[33]  A. Hezel,et al.  Phase 2 study of MK‐2206, an allosteric inhibitor of AKT, as second‐line therapy for advanced gastric and gastroesophageal junction cancer: A SWOG cooperative group trial (S1005) , 2015, Cancer.

[34]  M. Clausen,et al.  FDA-approved small-molecule kinase inhibitors. , 2015, Trends in pharmacological sciences.

[35]  I. Sohn,et al.  The NanoString-based multigene assay as a novel platform to screen EGFR, HER2, and MET in patients with advanced gastric cancer , 2015, Clinical and Translational Oncology.

[36]  Lisa A. Raedler Opdivo (Nivolumab): Second PD-1 Inhibitor Receives FDA Approval for Unresectable or Metastatic Melanoma. , 2015, American health & drug benefits.

[37]  C. Mathers,et al.  Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012 , 2015, International journal of cancer.

[38]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[39]  B. Chan,et al.  Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. , 2015, Translational lung cancer research.

[40]  D. Fabbro,et al.  Advances in kinase targeting: current clinical use and clinical trials. , 2014, Trends in pharmacological sciences.

[41]  Naotoshi Sugimoto,et al.  Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. , 2014, The Lancet. Oncology.

[42]  S. Park,et al.  Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second-line therapy for patients with advanced gastric cancer , 2014, Gastric Cancer.

[43]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of gastric adenocarcinoma , 2014, Nature.

[44]  Y. Bang,et al.  Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN--a randomized, phase III study. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  P. Tassone,et al.  A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer , 2014, British Journal of Cancer.

[46]  A. Bilici Treatment options in patients with metastatic gastric cancer: current status and future perspectives. , 2014, World journal of gastroenterology.

[47]  S. Akinaga,et al.  A phase II trial of a selective c-Met inhibitor tivantinib (ARQ 197) monotherapy as a second- or third-line therapy in the patients with metastatic gastric cancer , 2014, Investigational New Drugs.

[48]  H. Grabsch,et al.  FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study , 2014, British Journal of Cancer.

[49]  Jennifer Couzin-Frankel,et al.  Breakthrough of the year 2013. Cancer immunotherapy. , 2013, Science.

[50]  S. Chandarlapaty,et al.  A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors , 2013, Breast Cancer Research.

[51]  J. Ajani,et al.  Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  Ying Cheng,et al.  Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  L. Gianotti,et al.  Gastric Cancer Immunotherapy: An Overview , 2013 .

[54]  R. Pazdur,et al.  First FDA Approval of Dual Anti-HER2 Regimen: Pertuzumab in Combination with Trastuzumab and Docetaxel for HER2-Positive Metastatic Breast Cancer , 2013, Clinical Cancer Research.

[55]  Galina Kurteva,et al.  Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. , 2013, The Lancet. Oncology.

[56]  A. Wotherspoon,et al.  Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial , 2013, The Lancet. Oncology.

[57]  Sung-Bae Kim,et al.  Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. , 2013, The Lancet. Oncology.

[58]  J. Ji,et al.  FGFR2 Gene Amplification in Gastric Cancer Predicts Sensitivity to the Selective FGFR Inhibitor AZD4547 , 2013, Clinical Cancer Research.

[59]  P. Bonate,et al.  Phase II Study Evaluating 2 Dosing Schedules of Oral Foretinib (GSK1363089), cMET/VEGFR2 Inhibitor, in Patients with Metastatic Gastric Cancer , 2013, PloS one.

[60]  Razelle Kurzrock,et al.  A Multicenter Phase I Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors , 2012, Clinical Cancer Research.

[61]  T. Gajewski,et al.  Cancer immunotherapy , 2012, Molecular oncology.

[62]  D. Yim,et al.  Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum , 2012, British Journal of Cancer.

[63]  Khay Guan Yeoh,et al.  A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets , 2012, Gut.

[64]  A. Tolcher,et al.  The Clinical Effect of the Dual-Targeting Strategy Involving PI3K/AKT/mTOR and RAS/MEK/ERK Pathways in Patients with Advanced Cancer , 2012, Clinical Cancer Research.

[65]  T. Clackson,et al.  Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models , 2012, Molecular Cancer Therapeutics.

[66]  M. D’Elios,et al.  Novel Immunotherapeutic Strategies of Gastric Cancer Treatment , 2011, Journal of biomedicine & biotechnology.

[67]  J. Croxtall,et al.  Trastuzumab in HER2-Positive Metastatic Gastric Cancer , 2011, BioDrugs.

[68]  Yoon-Koo Kang,et al.  Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial , 2010, The Lancet.

[69]  P. Catalano,et al.  Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[70]  M. Shah,et al.  Assessment of two dosing schedules of GSK1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in metastatic gastric cancer (GC): Interim results of a multicenter phase II study. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[71]  D. Gerber,et al.  Targeted therapies: a new generation of cancer treatments. , 2008, American family physician.

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

[73]  L. Ellis,et al.  Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model , 2007, International journal of cancer.

[74]  C. Fenoglio-Preiser,et al.  Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[75]  S. Cowan-Jacob,et al.  Structural biology of protein tyrosine kinases , 2006, Cellular and Molecular Life Sciences CMLS.

[76]  A. Bardelli,et al.  Genetic analysis of the kinome and phosphatome in cancer , 2005, Cellular and Molecular Life Sciences CMLS.

[77]  R. Herrmann,et al.  Overview of monoclonal antibodies in cancer therapy: present and promise. , 2005, Critical reviews in oncology/hematology.

[78]  Neal J Meropol,et al.  Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[79]  Alex Matter,et al.  Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug , 2002, Nature Reviews Drug Discovery.

[80]  T. Foy,et al.  Designing HER2 vaccines. , 2002, Seminars in oncology.

[81]  E. Van Cutsem,et al.  Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[82]  J. Mendelsohn Blockade of receptors for growth factors: an anticancer therapy--the fourth annual Joseph H Burchenal American Association of Cancer Research Clinical Research Award Lecture. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[83]  N. Robert,et al.  Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[84]  H. Varmus,et al.  DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA , 1976, Nature.

[85]  E. Krebs,et al.  An adenosine 3',5'-monophosphate-dependant protein kinase from rabbit skeletal muscle. , 1968, The Journal of biological chemistry.

[86]  D. Deme,et al.  [Ramucirumab - a new anticancer agent]. , 2016, Orvosi Hetilap.

[87]  O. Abdel-Rahman Immune checkpoints aberrations and gastric cancer; assessment of prognostic value and evaluation of therapeutic potentials. , 2016, Critical reviews in oncology/hematology.

[88]  M. Clausen,et al.  Small-molecule kinase inhibitors: an analysis of FDA-approved drugs. , 2016, Drug discovery today.

[89]  A. Jimeno,et al.  Pembrolizumab: PD-1 inhibition as a therapeutic strategy in cancer. , 2015, Drugs of today.

[90]  Xin Huang,et al.  The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. , 2015, The Lancet. Oncology.

[91]  PD-1 inhibitor becomes "breakthrough therapy". , 2013, Cancer discovery.

[92]  H. Putter,et al.  Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. , 2010, The Lancet. Oncology.

[93]  E. Chiorean Bevacizumab in Combination With Chemotherapy As First-Line Therapy in Advanced Gastric Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase III Study , 2012 .

[94]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[95]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.