Searching for Achilles´ Heels of Cancer

The genetic and epigenetic events that drive tumorigenesis are highly complex and are critical determinants of treatment response. Although many tumor suppressors and oncogenes, and their relevant cellular pathways have been characterized in some detail, many aspects of cancer remain poorly understood. Critically, for most cancers the genetic diversity and complexity has hampered the development of efficient targeted therapies. To tackle the challenges of cancer treatment a new therapeutic approach is required. Attacking the weaknesses of cancer cells, as opposed to the strengths (i.e. the oncogenes that drive cancer), can provide highly effective and specific treatments. These cancer vulnerabilities or "Achilles` heels" can be the consequence of deregulated cellular pathways caused by tumorigenic events such as the loss of a tumor suppressor or the deregulation of an oncogene. The concept is derived from classical genetics and is referred to as synthetic sickness/lethality (SSL). Geneticists speak of a SSL interaction between two genes when a phenotype is only observed when both genes are inactivated. Importantly, this principle is also observed in mammalian cells and has been recently exploited to specifically target human cancer cells. However, these discoveries were made serendipitously and a methodical analysis of SSL in human cancer cells would therefore be invaluable. Recent technological advances, including RNAi, now allow biologists for the first time to develop methods to systematically explore synthetic lethality in mammalian cells The project described here offers a head-on method to identify synthetic lethal genetic inter-actions in cancer cells. It uses a combination of technologies including shRNA barcoding technology, assay multiplexing and compound library screens resulting in a unique and powerful method. To acquire mechanistic understanding of identified synthetic lethal interactions, functional validation and detailed follow-up studies will be a key component of this project. Together with a fingerprint of the genetic changes in patients` tumors, knowledge on the SSL interactions between cancer genes and drug targets is expected to contribute to patient-tailored therapies with few side effects.

The genetic and epigenetic events that drive tumorigenesis are highly complex and are critical determinants of treatment response. Although many tumor suppressors and oncogenes, and their relevant cellular pathways have been characterized in some detail, many aspects of cancer remain poorly understood. Critically, for most cancers the genetic diversity and complexity has hampered the development of efficient targeted therapies. Furthermore, tumor resistance is a major factor that limits therapeutic response. In this project we have developed and used a method to characterize thousands of gene-drug interactions in parallel. These interactions lie at the basis of response to treatment and their elucidation can thus contribute to the improvement of patient care. Specifically, work in this project has contributed to the discovery of a mechanism of resistance to a novel class of targeted therapeutics used in breast cancer that inhibit a signaling route known as the PI3K/mTOR pathway. In a follow-up study together with researchers at the MedUni Wien, these findings are now being tested in breast cancer patients. In addition, this work has paved the way for similar studies in other tumor types, including lung adenocarcinoma.