Using functional genetics to identify components of cancer relevant signaling pathways

Abstract

The clinical introduction of the so-called ‘targeted therapies’ some 15 years ago has started a new era in the treatment of cancer patients. These drugs hugely increase the possibilities to treat patients based on the genetic mutations of their cancer and therefore hold the promise of ‘personalized medicine’. However, resistance to these drugs is a major problem. New strategies to combat drug resistance are therefore urgently needed and much effort is put into understanding and uncovering mechanisms of drug resistance. In this thesis, the use of functional genetics is employed to identify components of cancer relevant signaling pathways. Knowledge of the complex functioning of such pathways could lead to the identification of new drug targets and the design of improved treatment strategies, for instance by combining multiple drugs to prevent or delay the onset of drug resistance. Chapter 1 is an introduction of the subjects that are relevant to this thesis. In chapter 2 the role of the growth factor HGF and its receptor MET in relation to drug resistance are discussed. Chapter 3 describes that inhibition of the tyrosine phosphatase PTPN11 is an excellent strategy to battle resistance to BRAF inhibitors that is cause by activation of Receptor Tyrosine Kinases. In chapter 4 MAML3 is identified as a factor that promotes resistance to retinoic acid in neuroblastoma. Chapter 5 describes that CTBP2 is involved in retinoic acid resistance. Finally, chapter 6 puts these findings into a broader perspective and the possibilities and problems of treating cancer patients on the basis of ‘personalized medicine’ are discussed.