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

Hendrika A. Segeren, Elsbeth A. van Liere, Frank M. Riemers, Alain de Bruin, Bart Westendorp*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    3 Downloads (Pure)

    Abstract

    Cancer cells often experience high basal levels of DNA replication stress (RS), for example due to hyperactivation of oncoproteins like MYC or RAS. Therefore, cancer cells are considered to be sensitive to drugs that exacerbate the level of RS or block the intra S-phase checkpoint. Consequently, RS-inducing drugs including ATR and CHK1 inhibitors are used or evaluated as anti-cancer therapies. However, drug resistance and lack of biomarkers predicting therapeutic efficacy limit efficient use. This raises the question what determines sensitivity of individual cancer cells to RS. Here, we report that oncogenic RAS does not only enhance the sensitivity to ATR/CHK1 inhibitors by directly causing RS. Instead, we observed that HRAS(G12V) dampens the activation of the P53-dependent transcriptional response to drug-induced RS, which in turn confers sensitivity to RS. We demonstrate that inducible expression of HRAS(G12V) sensitized cells to ATR and CHK1 inhibitors. Using RNA-sequencing of FACS-sorted cells we discovered that P53 signaling is the sole transcriptional response to RS. However, oncogenic RAS attenuates the transcription of P53 and TGF-beta pathway components which consequently dampens P53 target gene expression. Accordingly, live cell imaging showed that HRAS(G12V) exacerbates RS in S/G2-phase, which could be rescued by stabilization of P53. Thus, our results demonstrate that transcriptional control of P53 target genes is the prime determinant in the response to ATR/CHK1 inhibitors and show that hyperactivation of the MAPK pathway impedes this response. Our findings suggest that the level of oncogenic MAPK signaling could predict sensitivity to intra-S-phase checkpoint inhibition in cancers with intact P53.

    Original languageEnglish
    Pages (from-to)2719-2733
    Number of pages15
    JournalONCOGENE
    Volume41
    Issue number19
    DOIs
    Publication statusPublished - 6-May-2022

    Keywords

    • DNA-DAMAGE
    • GENOMIC INSTABILITY
    • SIGNALING PATHWAYS
    • TGF-BETA
    • CANCER
    • EXPRESSION
    • CYCLE
    • ATR
    • ACTIVATION
    • DYNAMICS

    Cite this