DNA Replication Stress and Cancer
Cancer is a disease uniquely characterized by deregulated cell proliferation, genomic instability and clonal evolution. Our laboratory, together with the laboratories of Professors Vassilis Gorgoulis and Jiri Bartek, has proposed a model to link the key characteristics of cancer cited above. Specifically, we have proposed that activated oncogenes, in the process of driving cell proliferation, induce DNA replication stress. This oncogene-induced DNA replication stress (OiRS), a feature of most cancers, leads to DNA replication errors that render the genome of cancer cells unstable. We propose that OiRS is a major driver of cancer development. Activation of an oncogene, that occurs as a first step in cancer development, results in genomic instability that allows more mutations to accumulate. Some of these mutations will be oncogenic, fueling further cancer growth and higher levels of genomic instability, while other mutations confer other properties, such as metastasis and resistance to therapy, that make cancers so hard to treat. Our model, therefore, describes a vicious circle that may help explain cancer development.
Since the discovery of OiRS, more than twenty years ago, our laboratory has focused on studying the mechanisms by which oncogenes induce DNA replication stress, the types of mutations present in cancers, what fraction of these mutations can be attributed to OiRS, as well as identifying weak spots for therapeutic intervention. We anticipate that inhibiting repair of the damage that oncogenes inflict on the replication machinery of cancer cells would render cancer cells unable to complete replication of their genome, leading to cell death. We have made great progress addressing each of these aims. Our ultimate goal is to make some tangible contribution towards the development of better cancer therapies.
