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Synthetic viability of homologous recombination-deficient cancers

Periodic Reporting for period 2 - SYNVIA (Synthetic viability of homologous recombination-deficient cancers)

Reporting period: 2018-01-01 to 2019-06-30

Although various effective anti-cancer treatments have become available over the last decades, therapy resistance remains the major cause of death of cancer patients with disseminated tumors. Striking examples are patients with tumors that are defective in the repair of DNA double strand breaks by homologous recombination (HR). Due to this defect, the patients initially show high response rates to DNA damage-inducing cancer therapy. Unfortunately, the development of resistance of primary or disseminated tumors eventually emerges, which minimizes therapeutic options and greatly reduces survival. It is therefore crucial to understand the molecular mechanisms underlying this therapy escape in order to impact the current annual cancer mortality of about 2 million persons in Europe.
The overall goal of the SYNVIA project is to target the clinical hurdle of anti-cancer therapy resistance. For this purpose, we have addressed the problem of therapy escape by using powerful genetically engineered mouse models of breast cancer deficient in the tumor suppressor genes BRCA1- and BRCA2, which closely mimic the human disease. Due to the BRCA inactivation, the tumors that arise lack HR-directed DNA repair. Similar to the situation in cancer patients, we observed that cancer cells in these models eventually escape the deadly effects of chemotherapy or novel targeted drugs. Thus, these resistance models provide a unique opportunity to explore therapy escape mechanisms.
By synergizing the advantages of next generation sequencing with functional genetic screens in our tractable model systems, we have identified novel mechanisms that cause resistance of HR-deficient cancers by the loss of another gene (“synthetic viability”).
Our BRCA1/2 models are not only tools to understand therapy escape mechanisms, but they have also yielded basic knowledge about DNA repair pathways and the mechanism of action of inhibitors of the enzyme poly-ADP ribose polymerase (PARP), which helps damaged cells repair themselves and could be exploited in a targeted therapeutic approach. Moreover, the alterations that render cells resistant to such targeted therapies may cause new synthetic dependencies that we aim to exploit in the second half of the project.