Point mutations of protein kinases and individualised cancer therapy.
The treatment of cancer is rapidly changing, with an increasing focus on converting our improved understanding of the molecular basis of disease into clinical benefit for patients. Protein kinases that are mutated in cancer represent attractive targets, as they may result in cellular dependency on the mutant kinase or its associated pathway for survival, a condition known as 'oncogene addiction'. Early clinical experiences have demonstrated dramatic clinical benefit of targeting oncogenic mutations in diseases that have been largely resistant to traditional cytotoxic chemotherapy. Further, mutational activation of kinases can indicate which patients are likely to respond to targeted therapeutics. However, these experiences have also illuminated a number of critical challenges that will have to be addressed in the development of effective drugs across different cancers, to fully realise the potential of individualised molecular therapy. This review utilises examples of genetic activation of kinases to illustrate many of the lessons learned, as well as those yet to be implemented.
Davies
Michael
M
University of Texas--M D Anderson Cancer Center, Department of Medical Oncology, 1515 Holcombe Blvd, Unit 10, Houston, TX 77030, USA. mdavies@mdanderson.org
Hennessy
Bryan
B
Mills
Gordon B
GB
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases