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

Abstract

Cancer is a collective term for many different diseases. There are more than a 100 different types of cancer, each of which can be considered a different disease that requires its own treatment due to its unique characteristics. What all cancers have in common, however, is that cancer is primarily a genetic disease that can be caused by changes in the DNA, also known as mutations, that eventually lead to the production of mutated proteins and the dysregulation of cellular processes such as cell division, growth, migration, and survival. Such mutations in the DNA can occur 'spontaneously' as well as due to external factors such as smoking and UV radiation. Cancer cells that contain 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. 'Precision medicine' or 'targeted therapy' uses targeted cancer drugs ('magic bullets') that specifically block the mutated proteins on which the cancer cell depends. As a result of this personalized approach to cancer, cancer patients can receive individual treatment based on the unique mutation profile of their tumor. This increases the chance of success of the treatment and reduces the risk of side effects. In addition, targeted therapy is generally less harmful and results in superior progression-free survival compared to conventional chemotherapy.

One of the first examples, and also the most successful example of this concept, is the specific blocking of the fused BCR-ABL protein by the drug imatinib in patients with chronic myeloid leukemia. This targeted approach has resulted in a massive increase in 10-year survival rate. Before the targeted cancer drug imatinib was used, less than 20% of patients were still alive 10 years after diagnosis. This survival rate has increased to about 83% with the imatinib treatment. As a result, the use of targeted cancer drugs seemed like a 'miracle cure' for cancer. Unfortunately, this approach was not as successful for most other cancers, and the initial enthusiasm and expectations of the use and development of targeted cancer drugs had to be adjusted. Cancer patients generally experience short-term relief due to resistance to the targeted cancer drugs which 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 to survive despite inhibition of the mutant 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. The focus of this thesis is to 'combine and conquer' as a strategy for the treatment of cancer and to study why cancer cells are resistant to certain targeted therapies.