Resistance to genotoxic drugs is the major cause of cancer therapy failure. In the past, E2F1 was recognized as a key regulator of apoptosis, but the latest evidence reveals that this transcription factor is aberrantly high in late-stage cancers and instead of apoptosis promotes tumor invasion and metastasis. This newly discovered activity of deregulated E2F1 reflects a cell context-dependent loss of its death-inducing function. We highlight the role of E2F1 in drug resistance by focusing on recent advances in elucidating the molecular mechanisms that counteract E2F1-induced apoptosis signaling in damaged cells. These mechanisms explain the paradox of high E2F1 expression in advanced tumors, highlight potential loopholes for cancers to escape from conventional treatment, and imply novel therapeutic strategies.
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