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

Murga, Matilde; Campaner, Stefano; López-Contreras, Andrés J.; Toledo, Luis I.; Soria, Rebeca; Montaña, Maria F; D’Artista, Luana; Schleker, Thomas; Guerra, Carmen; García, Elena; Barbacid, Mariano; Hidalgo, Manuel; Amati, Bruno; Fernández-Capetillo, Óscar

doi:10.1038/nsmb.2189

Cited by 367 publications

(358 citation statements)

References 49 publications

(65 reference statements)

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“…These results suggested that low levels of ATR could also be particularly toxic in the context of other mutations that promote DNA replication. Accordingly, subsequent studies showed that low levels of ATR prevented the onset of Myc- induced Burkitt lymphomas in mice [10], a tumour type that presents high level of RS. Besides Myc, reduced levels of ATR were also shown to be particularly limiting for leukemias initiated by an MLL-ENL translocation or for H-Ras driven p53-null fibrosarcomas [11].…”

Section: Targeting Rs In Cancer Treatmentmentioning

confidence: 99%

“…One limitation of this strategy is the lack of appropriate biomarkers of RS that work on clinically relevant samples. So far, pan-nuclear histone H2AX phoshorylation has been used as a surrogate marker, given that it is restricted to S-phase cells and is detected in cells that show RPA foci [10,[81][82][83]. An interesting alternative is the detection of 53BP1 bodies, large nuclear 53BP1 foci which accumulate preferentially at fragile sites in G1 cells after exposure to RS [84,85].…”

Section: Targeting Rs In Cancer Treatmentmentioning

confidence: 99%

“…While most data with ATR inhibitors so far relates to in vitro studies due to the limited availability of ATR inhibitors that can work in vivo, some of the observations from ATR mutant mouse models could be validated with Chk1 inhibitors. First, Chk1 inhibitors showed efficacy on the treatment of Myc-lymphoma xenografts [10,76]. In addition, high levels of Chk1 are induced by N-Myc in a xenograft model of neuroblastoma, making the tumours highly sensitive to the treatment with Chk1 inhibitors [92,93].…”

Section: Targeting Rs In Cancer Treatmentmentioning

confidence: 99%

“…In contrast to other genomic instability syndromes that show cancer predisposition, ATR-Seckel mice do not develop spontaneous tumours. In fact, reduced levels of ATR prevent the onset of certain tumours such as Myc-induced B cell lymphomas or MLL-ENL driven acute myeloid leukemias [10,11]. We believe that the increased sensitivity of cancer cells towards limited activity of ATR is linked to the increased levels of RS that are associated with oncogene expression, which renders these cells highly dependant on a proficient RS-checkpoint.…”

Section: Introductionmentioning

confidence: 98%

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Replication stress and cancer: It takes two to tango

Lecona

Fernández-Capetillo

2014

Experimental Cell Research

119

107

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Problems arising during DNA replication require the activation of the ATR-CHK1 pathway to ensure the stabilization and repair of the forks, and to prevent the entry into mitosis with unreplicated genomes. Whereas the pathway is essential at the cellular level, limiting its activity is particularly detrimental for some cancer cells. Here we review the links between replication stress (RS) and cancer, which provide a rationale for the use of ATR and Chk1 inhibitors in chemotherapy. First, we describe how the activation of oncogene-induced RS promotes genome rearrangements and chromosome instability, both of which could potentially fuel carcinogenesis. Next, we review the various pathways that contribute to the suppression of RS, and how mutations in these components lead to increased cancer incidence and/or accelerated ageing. Finally, we summarize the evidence showing that tumours with high levels of RS are dependent on a proficient RS-response, and therefore vulnerable to ATR or Chk1 inhibitors.

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Section: Targeting Rs In Cancer Treatmentmentioning

confidence: 99%

Section: Targeting Rs In Cancer Treatmentmentioning

confidence: 99%

Section: Targeting Rs In Cancer Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Replication stress and cancer: It takes two to tango

Lecona

Fernández-Capetillo

2014

Experimental Cell Research

119

107

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“…Recently, it has been shown that oncogene-induced replicative stress can be used to selectively kill tumor cells. 42 Tumors with high levels of replicative stress, such as the ones generated by Myc overexpression, are specifically susceptible to genotoxic drugs that impair the DNA damage response …”

Section: Cdk4(r/r); P21(+/-); P27(+/-) Cdk4(r/r); P21(-/-); P27(-/-)mentioning

confidence: 99%

An essential role for Ink4 and Cip/Kip cell-cycle inhibitors in preventing replicative stress

Quereda

Porlan

Cañamero³

et al. 2015

Cell Death Differ

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Cell-cycle inhibitors of the Ink4 and Cip/Kip families are involved in cellular senescence and tumor suppression. These inhibitors are individually dispensable for the cell cycle and inactivation of specific family members results in increased proliferation and enhanced susceptibility to tumor development. We have now analyzed the consequences of eliminating a substantial part of the cell-cycle inhibitory activity in the cell by generating a mouse model, which combines the absence of both p21 Cip1 and p27 Kip1 proteins with the endogenous expression of a Cdk4 R24C mutant insensitive to Ink4 inhibitors. Pairwise combination of Cdk4 R24C, p21-null and p27-null alleles results in frequent hyperplasias and tumors, mainly in cells of endocrine origin such as pituitary cells and in mesenchymal tissues. Interestingly, complete abrogation of p21 Cip1 and p27 Kip1 in Cdk4 R24C mutant mice results in a different phenotype characterized by perinatal death accompanied by general hypoplasia in most tissues. This phenotype correlates with increased replicative stress in developing tissues such as the nervous system and subsequent apoptotic cell death. Partial inhibition of Cdk4/6 rescues replicative stress signaling as well as p53 induction in the absence of cell-cycle inhibitors. We conclude that one of the major physiological activities of cell-cycle inhibitors is to prevent replicative stress during development.

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Resistance to DNA repair inhibitors in cancer

et al. 2022

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The DNA damage response (DDR) represents a complex network of proteins which detect and repair DNA damage, thereby maintaining the integrity of the genome and preventing the transmission of mutations and rearranged chromosomes to daughter cells. Faults in the DDR are a known driver and hallmark of cancer. Furthermore, inhibition of DDR enzymes can be used to treat the disease. This is exemplified by PARP inhibitors (PARPi) used to treat cancers with defects in the homologous recombination DDR pathway. A series of novel DDR targets are now also under pre-clinical or clinical investigation, including inhibitors of ATR kinase, WRN helicase or the DNA polymerase/helicase Polh (Pol-Theta). Drug resistance is a common phenomenon that impairs the overall effectiveness of cancer treatments and there is already some understanding of how resistance to PARPi occurs. Here, we discuss how an understanding of PARPi resistance could inform how resistance to new drugs targeting the DDR emerges. We also discuss potential strategies that could limit the impact of these therapy resistance mechanisms in cancer.Abbreviations ATR, Ataxia telangiectasia and Rad3 related gene; BRCA1, BRCA1 DNA repair-associated gene; BRCA2, BRCA2 DNA repair-associated gene; ctDNA, circulating tumour DNA; DDR, DNA damage response network; HR, homologous recombination; MMR, mismatch DNA repair; NAD+, nicotinamide adenine dinucleotide; PAR, poly-ADP-ribose; PARP1, poly-(ADP-ribose) polymerase 1 gene; PARPi, PARP inhibitor; POLQ, DNA polymerase theta gene, protein known as Polh; RS, replication stress; SWI/SNF, SWItch/sucrose non-fermentable chromatin remodelling complex; TMEJ, theta-mediated end joining; VEGF, vascular endothelial growth factor; WGR, protein domain containing tryptophan (W), glycine (G), arginine (R); WRN, Werner syndrome ATP-dependent helicase gene; ZnF, Zinc Finger protein domain.

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

Cited by 367 publications

References 49 publications

Replication stress and cancer: It takes two to tango

Replication stress and cancer: It takes two to tango

An essential role for Ink4 and Cip/Kip cell-cycle inhibitors in preventing replicative stress

Resistance to DNA repair inhibitors in cancer

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