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Targeting the fanconi anemia pathway to identify tailored anticancer therapeutics.

Jenkins C, Kan J, Hoatlin ME - Anemia (2012)

Bottom Line: The Fanconi Anemia (FA) pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs).The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways.Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, 3181 SW Sam Jackson Parkway, Portland, OR 97239, USA.

ABSTRACT
The Fanconi Anemia (FA) pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs). The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways. Selective killing of cancer cells with an intact FA pathway but deficient in certain other DNA repair pathways is an emerging approach to tailored cancer therapy. Inhibiting the FA pathway becomes selectively lethal when certain repair genes are defective, such as the checkpoint kinase ATM. Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

No MeSH data available.


Related in: MedlinePlus

PTEN defects in cancers. Types of cancer diagnosed annually in the US (orange oval), with the estimates for PTEN deficiencies shown in each type (blue oval). An unknown percentage of tumors with PTEN deficiencies will have a defect in homologous recombination (HR) repair, predicting sensitivity to treatment with PARP1 inhibitors (green oval).
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fig2: PTEN defects in cancers. Types of cancer diagnosed annually in the US (orange oval), with the estimates for PTEN deficiencies shown in each type (blue oval). An unknown percentage of tumors with PTEN deficiencies will have a defect in homologous recombination (HR) repair, predicting sensitivity to treatment with PARP1 inhibitors (green oval).

Mentions: PTEN (phosphatase and tensin homolog) is a tumor-suppressor gene and one of the most commonly mutated genes in human tumor cells [38, 39] (see Figure 2). PTEN deficiency results in decreased expression of RAD51, which is required for homologous recombination [38, 40]. PTEN deficient tumors are thus candidates for targeted therapy by PARP1 inhibition [36, 38]. Although approximately 470,000 (48%) of 977,628 newly diagnosed cancers each year in the US may have PTEN defects, only a subset of these cancers will have PTEN mutations that result in homologous recombination defects and sensitivity to PARP inhibitors [28, 39, 41–51]. Current studies are aimed at determining the relationship between PTEN loss, RAD51 expression, and PARP1 inhibitor sensitivity [36]. Efforts to asses HR status to establish which PTEN mutations lead to an HR defect, and determining under what circumstances RAD51 expression could be used as a biomarker, will be useful to stratify and predict PARP1 inhibitor sensitivity.


Targeting the fanconi anemia pathway to identify tailored anticancer therapeutics.

Jenkins C, Kan J, Hoatlin ME - Anemia (2012)

PTEN defects in cancers. Types of cancer diagnosed annually in the US (orange oval), with the estimates for PTEN deficiencies shown in each type (blue oval). An unknown percentage of tumors with PTEN deficiencies will have a defect in homologous recombination (HR) repair, predicting sensitivity to treatment with PARP1 inhibitors (green oval).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368156&req=5

fig2: PTEN defects in cancers. Types of cancer diagnosed annually in the US (orange oval), with the estimates for PTEN deficiencies shown in each type (blue oval). An unknown percentage of tumors with PTEN deficiencies will have a defect in homologous recombination (HR) repair, predicting sensitivity to treatment with PARP1 inhibitors (green oval).
Mentions: PTEN (phosphatase and tensin homolog) is a tumor-suppressor gene and one of the most commonly mutated genes in human tumor cells [38, 39] (see Figure 2). PTEN deficiency results in decreased expression of RAD51, which is required for homologous recombination [38, 40]. PTEN deficient tumors are thus candidates for targeted therapy by PARP1 inhibition [36, 38]. Although approximately 470,000 (48%) of 977,628 newly diagnosed cancers each year in the US may have PTEN defects, only a subset of these cancers will have PTEN mutations that result in homologous recombination defects and sensitivity to PARP inhibitors [28, 39, 41–51]. Current studies are aimed at determining the relationship between PTEN loss, RAD51 expression, and PARP1 inhibitor sensitivity [36]. Efforts to asses HR status to establish which PTEN mutations lead to an HR defect, and determining under what circumstances RAD51 expression could be used as a biomarker, will be useful to stratify and predict PARP1 inhibitor sensitivity.

Bottom Line: The Fanconi Anemia (FA) pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs).The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways.Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, 3181 SW Sam Jackson Parkway, Portland, OR 97239, USA.

ABSTRACT
The Fanconi Anemia (FA) pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs). The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways. Selective killing of cancer cells with an intact FA pathway but deficient in certain other DNA repair pathways is an emerging approach to tailored cancer therapy. Inhibiting the FA pathway becomes selectively lethal when certain repair genes are defective, such as the checkpoint kinase ATM. Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

No MeSH data available.


Related in: MedlinePlus