for combining them with other targeted agents, in an attempt to overcome resistance. In the second part of the paper, masitinib c-Kit inhibitor we review MAPK targeted agents, focusing on their therapeutic potential in hematologic malignancies, and examine the prospects for combinations of MAPK inhibitors with cytotoxic agents or other signal transduction targeted agents to obtain synergistic anti tumour effects. Corresponding author: Michele Milella, Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi n. 53, 00144 Rome, Italy. Ph.: 39 06 52666919/6774, Fax: 39 06 52665637 e mail: [email protected]. Publisher,s Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that Brivanib FGFR inhibitor apply to the journal pertain. NIH Public Access Author Manuscript Drug Resist Updat. Author manuscript, available in PMC 2008 September 23. Published in final edited form as: Drug Resist Updat. 2007 June, 10: 81 100. doi:10.1016/j.drup.2007.03.003. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript Keywords Targeted therapy, drug resistance, combination therapy, molecular markers, EGFR, IGFR1, MAPK, MEK inhibitors, AML 1.
Introduction The term,targeted therapy, refers to a new generation of cancer drugs designed to interfere with a specific molecular target, typically a protein, believed to have a critical role in tumour growth or progression. The clinical success of the small molecule tyrosine kinase inhibitor imatinib mesylate in chronic myeloid leukaemia and gastrointestinal stromal tumours has established a paradigm for the treatment of tumours whose growth is critically dependent on specific kinase targets. Indeed, CML is driven by the mutant kinase fusion protein BCR ABL, which contains a constitutively activated ABL kinase, while GIST are caused by activating point mutations in the c KIT or platelet derived growth factor receptor kinases. Imatinib effectively blocks the activity of all three kinases and produces dramatic clinical responses in all three clinical situations in a manner that correlates precisely with the presence of these mutations in the tumour.
Encouraging clinical studies have opened the approval path to other targeted agents: the epidermal growth factor receptor inhibitor erlotinib in non small cell lung cancer , the multikinase inhibitors sunitinib in advanced renal cell cancer, and the dual EGFR HER2 TK inhibitor lapatinib in HER2 positive, Trastuzumabresistant, advanced breast cancer. However, other compounds that specifically target protein kinases have been much less successful in the clinical, especially when combined with classical cytotoxic agents. These setbacks reflect a variety of factors, including a rush to get compounds into the clinic, a lack of validated biomarkers, insufficient characterization of patient populations appropriate for treatment, and oversight of pharmacodynamic and scheduling issues. One important point to keep in mind is that a single genetic alteration necessary and sufficient to drive the array of phenotypic hallmarks of malignancy is the exception rather than the rule in human tumours, thei