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GENE-12. EMERGINGPRINCIPLES OFSYNTHETIC LETHALITYIN GLIOBLASTOMA Pia HoellerbauerSonali AroraHeather Feldman2017 год

GENE-12. EMERGING PRINCIPLES OF SYNTHETIC LETHALITY IN GLIOBLASTOMA
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Полный текстСтраница публикацииПубликация в OpenAlex
Аннотация: Synthetic lethality occurs when mutations in two otherwise non-essential genes are combined to cause lethality. Because cancer is a disease of genetic alteration, synthetic lethality has been heralded as a method to identity candidate therapeutic targets, e.g., where a target gene could be “synthetic lethal” with a cancer driver mutation. To define synthetic lethal relationships in glioblastoma (GBM), we have performed multiple focused set and genome-wide CRISPR-Cas9 and RNAi lethality screens in patient-derived GBM stem-like cells (GSCs) and non-transformed human neural progenitor cells. Because GSCs isolates likely represent a sub-clone of the original tumor and we can determine GSCs’ genetic and epigenetic make up, it is possible to address the concept of synthetic lethality for GBM. To this end, we recently performed comprehensive CRISPR-Cas9 retests of all scoring GBM lethal genes (>900) from screens in three patient isolates with different and overlapping genetic drivers. We then performed secondary retests of high priority gene targets in 13 GSC harboring various alterations commonly found in GBMs, e.g., EGFRamp, NF1mut, PIK3CAmut, PTENloss/mut, TP53mut, etc. The results were surprising, first in what we did not find. We failed to find synthetic lethal targets for RB1mut, TERT expression, or TP53loss/mut, suggesting that synthetic lethal relationships for these alterations may not exist for GBM. Second, NF1mut interactors defined a broader class of synthetic lethal targets with over activity of the RTK/Ras pathway, which can arise from various activating lesions. Third, candidate “clean” synthetic lethal relationships can be observed, but, so far, only with EGFRamp, MYC/MYCNamp, and, possibly, PTEN/PIK3CA alterations. Thus, in general, our results suggest that the majority of synthetic lethal relationships in GBM arise from oncogenic activation of the RTK/Ras and PI-3 kinase pathway or amplification of MYC/MYCN. (Synthetic lethal targets will be revealed and discussed at the meeting.)
Год издания: 2017
Авторы: Pia Hoellerbauer, Sonali Arora, Heather Feldman, Lucas Carter, Emily J. Girard, Philip Corrin, James M. Olson, Patrick J. Paddison
Издательство: Oxford University Press
Источник: Neuro-Oncology
Ключевые слова: CRISPR and Genetic Engineering
Другие ссылки: Neuro-Oncology (PDF)
Neuro-Oncology (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)