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Oncogenic RAS sensitizes cells to drug-induced replication stress via transcriptional silencing of P53

ABSTRACT: Since oncogenes induce DNA replication stress (RS), cancer cells rely on the intra S-phase checkpoint for survival. Consequently, RS inducing drugs and ATR and CHK1 inhibitors are exploited as anti-cancer therapy. However, drug resistance limits efficient use. This raises the question what determines sensitivity of individual cancer cells to RS. Here, we report that oncogenic RAS dampens the P53 checkpoint which confers sensitivity to RS. We demonstrate that inducible expression of HRASG12V leads to mild RS in RPE-hTERT cells and was sufficient to sensitize cells to ATR and CHK1 inhibitors. Using RNA-sequencing we discovered that P53 signaling is essential for the response to RS. However, oncogenic RAS attenuates transcription of P53 and its target genes. Accordingly, live cell imaging shows that HRASG12V exacerbates RS in S/G2-phase. Thus, our results suggest that hyperactivation of the MAPK pathway could predict durable responses to RS inducing drugs in cancer patients

ORGANISM(S): Homo sapiens

PROVIDER: GSE168987 | GEO | 2022/04/05

REPOSITORIES: GEO

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