Abstract

Cancer is largely a disease driven by the acquisition and selection of somatic genetic mutations leading to the gain and loss-of-function of critical oncogenes and tumour suppressors.  The elucidation of the first human genome sequence coupled with the advent of Next Generation Sequencing has made it possible to fully elucidate all clonal and many sub-clonal genetic events in large numbers of cancers. In parallel, drug discovery efforts targeting key oncogenes including BCR-ABL, HER2, BRAF, EGFR and KIT, among many others, have led to a new class of therapeutics showing marked clinical activity in diseases previously refractory to standard cytotoxic agents. The full realisation of this paradigm, however, will require solving a number of key problems. Among these are enhancing our ability to drug difficult protein targets, elaborating therapeutics that take advantage of synthetic lethal nodes in tumour suppressor pathways and understanding therapeutic resistance as a starting point for the development of curative combination therapy. In parallel, clinical trials design must advance to allow us to rapidly identify the most effective dose and schedule for new drugs and new drug combinations.