Transcription takes the wheel in the replication stress response: the road to drug sensitivity and resistance

Activation of oncogenes in cancer cells causes endogenous DNA replication stress (RS). RS is defined as errors during DNA-replication and is present in the vast majority of cancer cells. As a result, cancer cells are sensitive to additional DNA damage and heavily rely on the intra S-phase checkpoint for survival. Therefore, RS-inducing chemotherapeutics have been the mainstay of anti-cancer treatment for decades. Moreover, inhibitors against key players of the intra S-phase checkpoint, ATR and CHK1, are currently evaluated in clinical trials. Despite these developments, resistance to RS-inducing drugs is a major problem. This suggests that some cancer cells can resist potential severe levels of RS. However, the underlying mechanisms are not well understood. To identify the strategies employed by cancer cells to resist therapy, we studied the response of individual cancer cells to RS-inducing drugs. We found that cancer cells exhibit elevated levels of E2F regulated genes. This allows cell proliferation despite RS. Furthermore, we discovered that the frequently occurring oncogenic version of RAS transcriptionally dampens an important control pathway. As a result, cancer cells with oncogenic RAS are sensitive to RS-inducing drugs. Last, using a novel strategy, we uncovered that high expression of a subset of genes potentially protects cancer cells from drugs that induce RS. Overall, the data presented in this thesis imply a key role for transcription in resistance and sensitivity to drug-induced RS.