Precision Medicine and Cancer: Challenges and Opportunities

Since the discovery of the first human oncogene in 1982, scientists have identified dozens of genes directly implicated in the development of human tumors. This wealth of information has led to the proposal that selective inhibition of these cancer genes will lead to a new paradigm in cancer treatment known as Precision Medicine. Indeed, since 1998, most anti-cancer drugs are either selective chemical or biological inhibitors of cancer genes. Yet, Precision Medicine has had a limited impact in the overall survival of cancer patients, especially those with advanced aggressive/metastatic tumors. Precision Medicine, albeit conceptually very attractive has several limitations that have tampered the enthusiasm that initially welcome this initiative. Some of these limitations include (i) the mutational complexity of advanced tumors and the large variety of cancer genes present in each of them, (ii) the fact that many of these cancer genes encode undruggable targets and (iii) the fact that many of these targets in the non-mutated form, are essential for normal homeostasis. Hence, tampering with them often lead to undesirable toxic effects that preclude the use of suitable drug combinations necessary to block the multiple signaling pathways often activated in advanced human tumors. I will discuss the inherent difficulties in identifying suitable therapeutic strategies focusing on two of the most common human cancer genes, the TP53 tumor suppressor and the KRAS oncogene. I will describe in some detail our efforts to identify suitable therapeutic targets for KRAS oncogenes suing classical genetic approaches in genetically engineered mouse models of lung and pancreatic adenocarcinoma that faithfully reproduce the natural history of the corresponding human cancers.