title: An overview of experimental and investigational multikinase inhibitors for the treatment of metastatic colorectal cancer.
abstract: BACKGROUND
  The era of molecular-targeted agents, particularly bevacizumab and cetuximab, has revolutionized the treatment paradigm for metastatic colorectal cancer (mCRC). Amongst the multikinase inhibitors (MKIs) examined, regorafenib was the first to establish its role in mCRC. Despite its modest efficacy, this finding had reignited interest in exploring MKIs with the hope of maximizing their therapeutic potential in mCRC.
  
  
  METHODS
  This review summarizes the previous studies of MKIs in mCRC, targeting two signaling pathways activated through vascular endothelial growth factor receptors and epidermal growth factor receptors. The article provides discussion with a focus on: the challenges encountered when combining MKI with chemotherapy, the lack of predictive markers, and strategies utilized to address escape pathways through combining MKIs with other targeted agents.
  
  
  CONCLUSIONS
  Clinical progress using MKIs in mCRC has been disappointing due to their limited efficacy. The exact role of regorafenib, apart from in chemo-refractory disease setting, requires further delineation. The role of MKIs in combination with other targeted agents or chemotherapy and in the maintenance setting is still considered experimental and warrants further investigation. The broader role of the current generation of MKIs will depend upon the accurate identification of patients with specific molecular phenotypes and better pharmacodynamic understanding of these agents to minimize toxicity.
authors.affiliation: a 1 Peter MacCallum Cancer Centre, Department of Medical Oncology , Melbourne, Australia +613 9656 1111 ; +613 9656 1135 ; yehchen.lee@petermac.org.
authors.forename: Yeh Chen
authors.initials: YC
authors.lastname: Lee
authors.affiliation: a 1 Peter MacCallum Cancer Centre, Department of Medical Oncology , Melbourne, Australia +613 9656 1111 ; +613 9656 1135 ; yehchen.lee@petermac.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Michael
authors.affiliation: a 1 Peter MacCallum Cancer Centre, Department of Medical Oncology , Melbourne, Australia +613 9656 1111 ; +613 9656 1135 ; yehchen.lee@petermac.org.|b 2 Monash University, School of Public Health and Preventive Medicine, Faculty of Medicine , Victoria, Australia.
authors.forename: John R
authors.initials: JR
authors.lastname: Zalcberg
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015195:Drug Design; D015507:Drugs, Investigational / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C559147:regorafenib
keywords: metastatic colorectal cancer; multikinase inhibitors; regorafenib; signalling cascade; tyrosine kinase inhibitor