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Disruption of SLX4-MUS81 Function Increases the Relative Biological Effectiveness of Proton Radiation.

ABSTRACT: PURPOSE:Clinical proton beam therapy has been based on the use of a generic relative biological effectiveness (RBE) of ?1.1. However, emerging data have suggested that Fanconi anemia (FA) and homologous recombination pathway defects can lead to a variable RBE, at least in vitro. We investigated the role of SLX4 (FANCP), which acts as a docking platform for the assembly of multiple structure-specific endonucleases, in the response to proton irradiation. METHODS AND MATERIALS:Isogenic cell pairs for the study of SLX4, XPF/ERCC1, MUS81, and SLX1 were irradiated at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer 2.5 keV/?m) or with 250 kVp x-rays, and the clonogenic survival fractions were determined. To estimate the RBE of the protons relative to cobalt-60 photons (Co60Eq), we assigned a RBE(Co60Eq) of 1.1 to x-rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor the damage responses, and the cell cycle distributions were assessed by flow cytometry. The poly(ADP-ribose) polymerase inhibitor olaparib was used for comparison. RESULTS:Loss of SLX4 function resulted in an enhanced proton RBE(Co60Eq) of 1.42 compared with 1.11 for wild-type cells (at a survival fraction of 0.1; P<.05), which correlated with increased persistent DNA double-strand breaks in cells in the S/G2 phase. Genetic analysis identified the SLX4-binding partner MUS81 as a mediator of resistance to proton radiation. Both proton irradiation and olaparib treatment resulted in a similar prolonged accumulation of RAD51 foci in SLX4/MUS81-deficient cells, suggesting a common defect in the repair of DNA replication fork-associated damage. CONCLUSIONS:A defect in the FA pathway at the level of SLX4 results in hypersensitivity to proton radiation, which is, at least in part, due to impaired MUS81-mediated processing of replication forks that stall at clustered DNA damage. In vivo and clinical studies are needed to confirm these findings in human cancers.

SUBMITTER: Liu Q

PROVIDER: S-EPMC4889010 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Disruption of SLX4-MUS81 Function Increases the Relative Biological Effectiveness of Proton Radiation.

Liu Qi Q Underwood Tracy S A TSA Kung Jong J Wang Meng M Lu Hsiao-Ming HM Paganetti Harald H Held Kathryn D KD Hong Theodore S TS Efstathiou Jason A JA Willers Henning H

International journal of radiation oncology, biology, physics 20160201 1

<h4>Purpose</h4>Clinical proton beam therapy has been based on the use of a generic relative biological effectiveness (RBE) of ∼1.1. However, emerging data have suggested that Fanconi anemia (FA) and homologous recombination pathway defects can lead to a variable RBE, at least in vitro. We investigated the role of SLX4 (FANCP), which acts as a docking platform for the assembly of multiple structure-specific endonucleases, in the response to proton irradiation.<h4>Methods and materials</h4>Isogen ...[more]

PMID: 27084631

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Project description:Background and purposeCarbon ion radiation therapy (CIRT) is recognized as an effective alternative treatment modality for early stage lung cancer, but a quantitative understanding of relative biological effectiveness (RBE) compared to photon therapy is lacking. In this work, a mechanistic tumor response model previously validated for lung photon radiotherapy was used to estimate the RBE of CIRT compared to photon radiotherapy, as a function of dose and the fractionation schedule.Materials and methodsClinical outcome data of 9 patient cohorts (394 patients) treated with CIRT for early stage lung cancer, representing all published data, were included. Fractional dose, number of fractions, treatment schedule, and local control rates were used for model simulations relative to standard photon outcomes. Four parameters were fitted: α, α/β, and the oxygen enhancement ratios of cells either accessing only glucose, not oxygen (OERI), or cells dying from starvation (OERH). The resulting dose-response relationship of CIRT was compared with the previously determined dose-response relationship of photon radiotherapy for lung cancer, and an RBE of CIRT was derived.ResultsBest-fit CIRT parameters were: α = 1.12 Gy-1 [95%-CI: 0.97-1.26], α/β = 23.9 Gy [95%-CI: 8.9-38.9], and the oxygen induced radioresistance of hypoxic cell populations were characterized by OERI = 1.08 [95%-CI: 1.00-1.41] (cells lacking oxygen but not glucose), and OERH = 1.01 [95%-CI: 1.00-1.44] (cells lacking oxygen and glucose). Depending on dose and fractionation, the derived RBE ranges from 2.1 to 1.5, with decreasing values for larger fractional dose and fewer number of fractions.ConclusionFitted radiobiological parameters were consistent with known carbon in vitro radiobiology, and the resulting dose-response curve well-fitted the reported data over a wide range of dose-fractionation schemes. The same model, with only a few fitted parameters of clear mechanistic meaning, thus synthesizes both photon radiotherapy and CIRT clinical experience with early stage lung tumors.

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Disruption of SLX4-MUS81 Function Increases the Relative Biological Effectiveness of Proton Radiation.

Publications

Disruption of SLX4-MUS81 Function Increases the Relative Biological Effectiveness of Proton Radiation.

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