Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors

Genomic Instability Group, Spanish National Cancer Research Centre, Madrid, Spain.
Nature Structural & Molecular Biology (Impact Factor: 13.31). 11/2011; 18(12):1331-5. DOI: 10.1038/nsmb.2189
Source: PubMed

ABSTRACT Oncogene-induced replicative stress activates an Atr- and Chk1-dependent response, which has been proposed to be widespread in tumors. We explored whether the presence of replicative stress could be exploited for the selective elimination of cancer cells. To this end, we evaluated the impact of targeting the replicative stress-response on cancer development. In mice (Mus musculus), the reduced levels of Atr found on a mouse model of the Atr-Seckel syndrome completely prevented the development of Myc-induced lymphomas or pancreatic tumors, both of which showed abundant levels of replicative stress. Moreover, Chk1 inhibitors were highly effective in killing Myc-driven lymphomas. By contrast, pancreatic adenocarcinomas initiated by K-Ras(G12V) showed no detectable evidence of replicative stress and were nonresponsive to this therapy. Besides its impact on cancer, Myc overexpression aggravated the phenotypes of Atr-Seckel mice, revealing that oncogenes can modulate the severity of replicative stress-associated diseases.

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Available from: Oskar Fdez-Capetillo, Feb 20, 2015
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    • "Replication stress (RS) leads to fork stalling as a result of nucleotide pool depletion and/or the generation of DNA lesions (Murga et al., 2011). RS triggers a DNA damage response (DDR) in an attempt to resolve the insult, ensure fork integrity, and restart DNA synthesis (Harper and Elledge, 2007). "
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    ABSTRACT: ATM-mediated signaling in response to DNA damage is a barrier to tumorigenesis. Here we asked whether replication stress could also contribute to ATM signaling. We demonstrate that, in the absence of DNA damage, ATM responds to replication stress in a hypoxia-induced heterochromatin-like context. In certain hypoxic conditions, replication stress occurs in the absence of detectable DNA damage. Hypoxia also induces H3K9me3, a histone modification associated with gene repression and heterochromatin. Hypoxia-induced replication stress together with increased H3K9me3 leads to ATM activation. Importantly, ATM prevents the accumulation of DNA damage in hypoxia. Most significantly, we describe a stress-specific role for ATM in maintaining DNA replication rates in a background of increased H3K9me3. Furthermore, the ATM-mediated response to oncogene-induced replication stress is enhanced in hypoxic conditions. Together, these data indicate that hypoxia plays a critical role in the activation of the DNA damage response, therefore contributing to this barrier to tumorigenesis.
    Molecular cell 11/2013; 52(5). DOI:10.1016/j.molcel.2013.10.019 · 14.46 Impact Factor
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    • "According to our studies, accentuated AURKA–PLK1 pathway activity may promote replication fork collapse and an increased dependence on ATR function. In this light, we and others recently demonstrated that oncogene expression increases reliance on ATR activity for genome stability and cancer cell viability (Gilad et al. 2010; Murga et al. 2011; Schoppy et al. 2012). By extension, it is possible that AURKA overactivation could both elevate the genomic instability of cancer cells through elevated fork collapse and increase the sensitivity of these cells to ATR/CHK1 inhibitors. "
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    ABSTRACT: The ATR-CHK1 axis stabilizes stalled replication forks and prevents their collapse into DNA double-strand breaks (DSBs). Here, we show that fork collapse in Atr-deleted cells is mediated through the combined effects the sumo targeted E3-ubiquitin ligase RNF4 and activation of the AURKA-PLK1 pathway. As indicated previously, Atr-deleted cells exhibited a decreased ability to restart DNA replication following fork stalling in comparison with control cells. However, suppression of RNF4, AURKA, or PLK1 returned the reinitiation of replication in Atr-deleted cells to near wild-type levels. In RNF4-depleted cells, this rescue directly correlated with the persistence of sumoylation of chromatin-bound factors. Notably, RNF4 repression substantially suppressed the accumulation of DSBs in ATR-deficient cells, and this decrease in breaks was enhanced by concomitant inhibition of PLK1. DSBs resulting from ATR inhibition were also observed to be dependent on the endonuclease scaffold protein SLX4, suggesting that RNF4 and PLK1 either help activate the SLX4 complex or make DNA replication fork structures accessible for subsequent SLX4-dependent cleavage. Thus, replication fork collapse following ATR inhibition is a multistep process that disrupts replisome function and permits cleavage of the replication fork.
    Genes & development 10/2013; 27(20):2259-73. DOI:10.1101/gad.223180.113 · 12.64 Impact Factor
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    • "In contrast to the augmentation of c-Myc driven tumorigenesis in mice lacking ATM or p53, the mutation or inhibition of ATR leads to the converse outcome of impaired tumor development (Murga et al., 2011). These results highlight the inherent differences in the cellular roles of the ATM and ATR signaling pathways and have suggested that ATR pathway inhibition has potential as a chemotherapeutic strategy, particularly in oncogene addicted tumors (Toledo et al., 2011; Schoppy et al., 2012). "
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    ABSTRACT: The DNA damage response (DDR) rapidly recognizes DNA lesions and initiates the appropriate cellular programs to maintain genome integrity. This includes the coordination of cell cycle checkpoints, transcription, translation, DNA repair, metabolism, and cell fate decisions, such as apoptosis or senescence (Jackson and Bartek, 2009). DNA double-strand breaks (DSBs) represent one of the most cytotoxic DNA lesions and defects in their metabolism underlie many human hereditary diseases characterized by genomic instability (Stracker and Petrini, 2011; McKinnon, 2012). Patients with hereditary defects in the DDR display defects in development, particularly affecting the central nervous system, the immune system and the germline, as well as aberrant metabolic regulation and cancer predisposition. Central to the DDR to DSBs is the ataxia-telangiectasia mutated (ATM) kinase, a master controller of signal transduction. Understanding how ATM signaling regulates various aspects of the DDR and its roles in vivo is critical for our understanding of human disease, its diagnosis and its treatment. This review will describe the general roles of ATM signaling and highlight some recent advances that have shed light on the diverse roles of ATM and related proteins in human disease.
    Frontiers in Genetics 03/2013; 4:37. DOI:10.3389/fgene.2013.00037
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