Cracking the ribosome code of drug resistance in sarcomas

Drug resistance is the biggest challenge in cancer therapy. It exists across all types of cancer and all modes of treatment. Understanding the underlying mechanisms by which cancer cells escape cell death is important for the design of effective and sustainable therapeutic interventions. This project seeks to establish selective protein translation as a novel mechanism of chemotherapeutic drug resistance. It is based on the hypothesis that heterogeneity in the composition of ribosomes (the ribosome code) affects translation in a cell-specific manner and enables some cancer cells to adapt swiftly to chemotherapy by acquiring a metastable phenotype of drug tolerance. The tentative concept of a ribosome code that controls protein translation refers to recent observations suggesting that differences in ribosomal protein composition biases certain ribosomes to preferentially regulate certain groups of genes. We anticipate that protein translational control may offer a regulatory mechanism that allows certain cancer cells to adapt their protein expression levels very rapidly, thereby acquiring short-term drug tolerance. More specifically, we propose that the heterogeneity of the ribosome code provides sufficient diversity to ensure that at least some cancer cells within a given tumor are able to survive the initial attack. This response may be not sustainable enough for long-term drug resistance, but it will allow a subset of cancer cells to temporally evade chemotherapy toxicity. These drug-tolerant persister cells create a window of opportunity for evolving more permanent forms of drug resistance (e.g., by accumulation of genetic mutation) upon prolonged drug exposure. We seek to prove (or refute) the existence of a ribosome code that confers short-term drug tolerance, which may constitute a critical first step for the evolution of genetic drug resistance, chemotherapy failure, and often the death of the patient. If our hypothesis is confirmed, it will establish a new resistance mechanism and open up novel therapeutic strategies to prevent genetic drug resistance by specific targeting of tolerance-conferring ribosomes. In this proof-of-concept study we will focus on pediatric sarcomas, which are almost always treated with chemotherapy and suffer from relatively poor outcome compared to other pediatric cancers. Using a combination of CRISPR activation screens and detailed investigation by ribosome footprinting, we will identify ribosome proteins that drive drug tolerance (which may constitute drug targets for combination therapy in pediatric sarcomas) and functionally link ribosome composition to the preferential translation of mRNAs relevant to drug tolerance. In summary this project promises to interrogate translational control as a drug tolerance mechanism, unravelling fundamental biological mechanisms. At the same time it has high therapeutic potential as it may propose combination therapies targeting the ribosome code.