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Abstract 1656: MK-1775 (WEE1 inhibition) lacks efficacy against DNA repair deficient pancreatic cancer cells
Conclusions: These results support a paradigm in which identified high risk FA/BRCA2-mutated patients would not benefit from WEE1 inhibitor monotherapy; and thus, would most likely respond better to conventional DNA damaging agent-based therapies (e.g., oxaliplatin or MMC).Citation Format: Shruti Lal, Saswati N. Chand, Emanuela Dylgjeri, Charles J. Yeo, Jordan M. Winter, Jonathan R. Brody. MK-1775 (WEE1 inhibition) lacks efficacy against DNA repair deficient pancreatic cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Phi...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Lal, S., Chand, S. N., Dylgjeri, E., Yeo, C. J., Winter, J. M., Brody, J. R. Tags: Experimental and Molecular Therapeutics Source Type: research

Abstract 3012: The Snm1B/Apollo DNA nuclease functions in resolution of replication stress and maintenance of genome stability
A critical aspect of normal cellular processes is the maintenance of genomic stability. Defects in cellular responses to DNA damage can lead to an accumulation of unrepaired or misrepaired lesions and ultimately, increased genome instability. Genomic DNA is constantly damaged through exposure to exogenous agents as well as during endogenous processes, including DNA replication. Progression of the replication fork can be impaired by structural or physical blocks leading to fork stalling. If stalled forks are not properly restarted or repaired, they can collapse, leading to chromosomal damage including breaks, deletions, and...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Das, I., Mason, J., Sekiguchi, J. Tags: Molecular and Cellular Biology Source Type: research

Abstract 3027: Investigating the function of NONO, a novel double strand break repair factor, and exploring its potential role as a biomarker for melanoma
We investigated the in vivo function of NONO, a protein that has been shown to promote a distinct sub-pathway of nonhomologous end joining (NHEJ) repair in vitro and in cultured cells. We used a gene trap strategy to create a null mutant for Nono, the mouse homolog of the human NONO gene. We investigated hematopoietic stem cells (HSCs), which are known to be sensitive to deficiencies in other DNA repair proteins. Nono-deficient mice showed reduced bone marrow and spleen cellularity. HSCs from Nono-deficient mice showed severe impairment in competitive repopulation assays in primary and secondary recipients. HSCs from Nono-...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Li, S., Shu, F., Khan, M. K., Pollack, B. P., Li, Z., McLemore, M., Dynan, W. S. Tags: Molecular and Cellular Biology Source Type: research

Abstract 820: Inhibition of Rad6 sensitizes triple negative breast cancer cells to platinum-based therapy
Treatment of triple negative breast cancers (TNBCs) poses a clinical challenge because they are not treatable with therapies targeting estrogen receptor and Her2/neu as they lack expression of estrogen, progesterone, and Her2/neu receptors. Since TNBCs share several histologic features with BRCA1-related breast cancer, and these breast cancers have aberrant DNA repair, DNA repair pathways are thought to play a role in TNBC development and drug response. Platinum (Pt)-based compounds induce toxic interstrand DNA crosslinks (ICL), the repair of which requires activities of BRCA/Fanconi anemia (FA) network and Rad6 postreplic...
Source: Cancer Research - September 30, 2014 Category: Cancer & Oncology Authors: Haynes, B., Sanders, M., Shekhar, M. Tags: Experimental and Molecular Therapeutics Source Type: research

Abstract 2380: Separate but important roles of {alpha}SpII and FANCD2 in the FA pathway after DNA interstrand crosslink damage
Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure, an increased incidence of cancer, genomic instability, congenital abnormalities and a defect in ability to repair DNA interstrand crosslinks (ICLs). We have previously shown that FA cells have a deficiency in the structural protein, nonerythroid alpha spectrin (SpII), which is critical for repair of DNA ICLs and binds to crosslinked DNA. The FA protein, FANCD2, after monoubiquitination (FANCD2-Ub), has also been shown to be critical for ICL repair. However, the relationship between SpII and FANCD2 and whether they are involved in the same steps...
Source: Cancer Research - September 30, 2014 Category: Cancer & Oncology Authors: Lambert, M. W., Sridharan, D., Zhang, P. Tags: Molecular and Cellular Biology Source Type: research