Repair of DNA lesions induced by platinum drugs

Projektbeschreibung

Einfluss des genetischen Hintergrunds auf die Chemotherapiewirksamkeit

Die Zellen gewährleisten durch verschiedene Mechanismen, die durch Arzneimittel oder ultraviolette Strahlung verursachte DNA-Schäden reparieren, die Genomstabilität. Einer dieser Mechanismen, die globale Genom-Nukleotidexzisionsreparatur, erkennt sperrige DNA-Läsionen überall im Genom unabhängig von der Transkription und repariert sie. Ziel des EU-finanzierten Projekts REAP ist zu verstehen, wie Mutationen im Signalweg der globalen Genom-Nukleotidexzisionsreparatur die Wirkung von Platin-Arzneistoffen wie Oxaliplatin und Cisplatin beeinflussen. Die Forschenden werden die Mutationen untersuchen, die diese unterschiedliche Erkennung von Platinläsionen durch globale Genom-Nukleotidexzisionsreparatur beeinflussen. Die gewonnenen Erkenntnisse werden dazu beitragen, die Behandlungsergebnisse der vorhandenen Chemotherapieprotokolle durch Erstellung genetischer Profile der von Krebs Betroffenen zu verbessern.

Ziel

DNA damage-inducing platinum drugs, such as oxaliplatin and cisplatin, are used to treat about half of all patients receiving chemotherapy. Although potentially very efficient, many patients develop resistance for yet unrecognized reasons. Better understanding of the DNA damage response (DDR) to platinum-DNA lesions is therefore much needed for improving treatment outcomes.
By performing DDR-dedicated CRISPR/Cas9 knockout screens, the applicant has shown that some cancer cells deficient in the major repair of bulky DNA lesions, global-genome nucleotide excision repair (GG-NER), are insensitive to oxaliplatin but sensitive to cisplatin. This striking difference remains as of yet unreported, but might explain differential responses of tumors to drugs. The aim of this proposal is to understand why GG-NER is unable to repair oxaliplatin lesions in particular genetic backgrounds. To do so, unbiased identification of genes differently mutated or expressed in oxaliplatin-sensitive versus insensitive cells will be followed by validation and in-depth functional characterization of identified targets. The ambition is to extrapolate experimental observations to translational knowledge. Validated targets will be studied in patient-derived tumor tissues as compared to nonmalignant tissues and related to patients’ treatment responses. Identification of genetic factors that regulate platinum lesions recognition by GG-NER will contribute to the understanding of molecular principles of platinum drugs cytotoxicity and might thus have considerable benefit on current cancer treatment schemes.
The novelty of the pilot data, the unique multidisciplinary design of the project, the use of state-of-the-art molecular techniques and a collaboration with multiple European experts will ensure high scientific impact. Both, the applicant and the host will greatly benefit from the vital knowledge transfer. This project follows the European Union's commitment to cancer research.