Exploiting genomic instability as an Achilles’ heel in cancer

Genomic instability is a hallmark of cancer for which an important cause is the DNA damage generated by oncogene-induced replication stress (RS). Genomically instable cancers increasingly depend on checkpoint kinases, including ATR and WEE1, to activate the DNA damage response, pointing towards therapeutic strategies that target elevated levels of RS as an Achilles’ heel in cancer. However, the cellular consequences of RS remain unclear, and tools to identify tumors with high levels of RS are lacking.
In this thesis we aimed to uncover the biological effects of oncogene-induced RS on tumor cells, uncover therapeutic opportunities of cancers that are characterized by high levels of RS, and develop tools to improve the identification of tumors with RS.
Immunohistochemical analysis of RS levels in relation to oncogene expression in breast cancer tissues, revealed that TNBCs exhibited the highest levels of RS, which were correlated with expression of the Cyclin E1 and c-Myc oncogenes.
In parallel, we studied the consequences of oncogene overexpression on replication kinetics and mitotic progression in experimental models, which show that Cyclin E1 or Cdc25A-induced RS leads to genomic instability, exacerbated by inhibition of ATR or WEE1.
Finally, we developed an mRNA expression-based signature for oncogene-induced RS to categorize tumors based on their RS levels, which identified DLBCL, ovarian cancer and TNBC as cancers with elevated RS.
Taken together, we have mapped the cellular consequences of oncogene-induced RS in experimental models and patient samples, and have developed a tool to facilitate patient selection for therapeutic approaches that target RS.