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The GFPIBD foci then slowly resolvedoverthenext hours.The increased IRIF persistence with higher IR dose suggests saturation of repair capacity or other damage responses.Neither the GFPIBD reporter nor ABT seemed to alter HAX localization or the recruitment of MDC and endogenous BP to IRIF. Nuclei indicated by, diamidinophenylindole. White columns, IR; gray columns, IR ABT.We next examined the potential mechanisms of growth suppression after IR ABT.At days after IR ABT, cells displaying persistent GFPIBD foci began to exhibit a morphology characteristic of senescence.When mice were treated with ABT twice daily for days before IR and then twice daily thereafter, we observed no increase in IRIF number at early time points but the number of cells with residual IRIF increased at hours.To compare in vivo growth delay with that observed in vitro, we performed a tumor regrowth experiment.A, dose response of IRIF formation in xenograft tumor cells hafter IR.Persistent cell cycle arrest and accelerated SDMA senescence are ascribed to accumulation of unrepaired DNA damage and chromatin perturbation, among other inducers. We speculate that the efficacy of PARP inhibitors toward homologous recombinationdeficient BRCA, BRCA, or PTEN negative cancer cells may similarly reflect a cellular response to accumulation of unrepaired endogenous DNA damage.Indeed, preliminary analysis of the PTEN mutant cell line PC suggests that ABT accelerates senescence, particularly in combination with radiation.Whereas it remains a dogma that IR and genotoxic agents mediate their lethal effects via enhanced apoptosis, necrosis, or mitotic catastrophe, senescence is an alternative terminal phenotype that may be highly relevant as a determinant of outcomes for cancer treatment. Discovery of the poly, PARP inhibitors may have a significant effect by inducing senescence as a novel SDMA mechanism for sensitization to radiation and chemotherapy.The costs of publication of this article were defrayed in part by the payment of page charges.Enhanced radiationinduced cellkill ing and prolongation of HAX foci expression by the histone deacetylase inhibitor MS.Published OnlineFirst July; DOI. Click on Request Permissions which will take you to the Copyright Clearance Centers Downloaded from on April. American Association for Cancer Research. To examine this observation and define the course of patients following TKI discontinuation, we systematically evaluated patients enrolled on clinical trials of agents to treat acquired resistance to erlotinib or gefitinib.Disease flare was defined as hospitalization or death attributable to disease progression during the washout period.The median time to disease flare after TKI discontinuation was days. Factors associated with disease flare included shorter time to progression on initial TKI. There was no association between disease flare and the presence of TM at the time of acquired resistance.Clinical trials in this patient population must minimize protocolmandated washout periods.EGFR mutations were first identified in lung cancer after clinical benefit to epidermal growth factor receptor. In patients with NSCLC whose tumors harbor an EGFR mutation, firstline tyrosine kinase inhibitor. Patients who initially benefit from erlotinib or gefitinib and then develop progression of disease are described as having acquired resistance. Despite this remarkable postprogression survival, we have noted that discontinuation of EGFR inhibition causes some patients to experience more rapid progression of symptoms, or a disease flare.

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