PhD Defense: Combine and conquer as a strategy to treat RAS-driven cancers

Cancer is a collective name for many different diseases. There are more than a 100 different types of cancer, each of which being considered a different disease that requires its own treatment due to its unique characteristics. However, what all cancer types have in common is that cancer is primarily a genetic disease that can be caused by changes in DNA, also called mutations, which ultimately lead to the production of mutated proteins and the disruption of cellular processes such as cell division, growth, migration and survival. Such mutations in the DNA can arise both 'spontaneously' and as a result of external factors such as smoking and UV radiation. Cancer cells containing such mutations in specific genes have generally become dependent on these mutations for their disrupted cell division and survival.

The discovery that cancer cells have generally become dependent on these mutations has led to the development of a whole new class of drugs and a breakthrough in cancer treatment. 'Personalized medicine' ('precision medicine' or 'targeted therapy') uses targeted cancer drugs ('magic bullets') that are aimed at specifically blocking the mutated proteins on which the cancer cell depends. This personal approach to cancer treatment allows cancer patients to receive individual treatment based on the unique mutation profile of their tumor. This increases the chance of success of the treatment and reduces the chance of side effects. Targeted therapy is also generally less harmful and results in superior progression-free survival compared to conventional chemotherapy.

One of the first and most successful examples of this concept is the specific blocking of the fused BCR-ABL protein by the cancer drug imatinib in patients with chronic myelogenous leukemia. This targeted approach has resulted in a huge increase in 10-year survival rate. Before the targeted cancer drug imatinib, less than 20% of patients were still alive 10 years after diagnosis. This survival rate has increased to approximately 83% with imatinib treatment. This made the use of targeted cancer drugs seem like a 'miracle cure' against cancer. Unfortunately, this approach did not prove as successful for most other cancer types and the initial enthusiasm and expectations for the use and development of targeted cancer drugs had to be adjusted. Cancer patients generally only experience short-term relief because resistance to targeted cancer drugs inevitably develops. By understanding how cancer cells are and/or become resistant to targeted cancer drugs, it is possible to significantly improve cancer treatment. Cancer cells often use so-called resistance pathways in order to survive despite the inhibition of the mutated protein. By also blocking this resistance pathway with a second cancer drug in combination with the first targeted drug, the cancer cell can no longer survive. 'Combine and conquer' as a strategy for the treatment of cancer and studying why cancer cells are resistant to certain targeted therapies is the focus of this thesis.