Radiosensitization with combined use of olaparib and PI-103 in triple-negative breast cancerReportar como inadecuado

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BMC Cancer

, 15:89

Experimental therapeutics and drug development


BackgroundTriple-negative breast cancer TNBC shows aggressive clinical behavior, but the treatment options are limited due to lack of a specific target. TNBC shares many clinical and pathological similarities with BRCA-deficient breast cancer, for which polyADP-ribose polymerase PARP inhibitor is effective, but PARP inhibitor alone failed to show clinical effects in patients with sporadic TNBC. Radiation induces DNA double-strand breaks, and the phosphoinositide 3-kinase PI3K signaling pathway has been known to regulate steady-state levels of homologous recombination. A recent preclinical study showed that PI3K inhibition impairs BRCA1-2 expression and sensitizes BRCA-proficient TNBC to PARP inhibition. Therefore, we assessed the radiosensitizing effect, and the underlying mechanism of combination treatment with PARP inhibitor olaparib and PI3K inhibitor PI-103 in BRCA-proficient TNBC cells.

MethodsMDA-MB-435S cells were divided into four treatment groups, irradiation IR alone, olaparib plus IR, PI-103 plus IR, and olaparib plus PI-103 plus IR. Cells were exposed to the drugs for 2 hours prior to irradiation, and the cell survival curve was obtained using a clonogenic assay. Western blotting and immunofluorescent detection of γH2AX foci were performed. Xenograft and bioluminescence imaging were carried out to assess in vivo radiosensitivity.

ResultsCombined use of olaparib and PI-103 enhanced radiation-induced death of MDA-MB-435S sensitizer enhancement ratioSER0.05,1.7 and MDA-MB-231-BR SER0.05,2.1 cells and significantly reduced tumor volume in a xenograft models P < 0.001. Treatment with PI-103 showed persistent γH2AX foci, indicating delayed repair of DNA strand breaks. PI-103 alone increased levels of polyADP-ribose and phosphorylated extracellular signal-regulated kinase, and downregulated BRCA1.

ConclusionsCombined use of olaparib and PI-103 enhanced radiation-induced cell death in BRCA-proficient MDA-MB-435S and MDA-MB-231-BR cells and xenografts. TNBC patients have high incidences of locoregional relapse and distant metastasis, and radiation therapy targets both locoregional control and treatment of distant recurrences such as brain metastasis or other oligometastasis. Targeting of the PI3K signaling pathway combined with PARP inhibition maybe a feasible approach to enhance effects of radiation in BRCA-proficient TNBC.

KeywordsTriple-negative breast cancer Radiotherapy Olaparib PI-103 PARP inhibitor PI3K inhibitor AbbreviationsTNBCTriple negative breast cancer

PARPPolyADP-ribose polymerase

PI3KPhosphoinositide 3-kinase


EREstrogen receptor

HER2Human epidermal growth factor 2

BERBase excision repair

HRHomologous recombination

DSBDouble-strand break

ERKExtracellular signal-regulated kinase

SERSensitizer enhancement ratio

SFSurviving fraction

SISynergistic index

RTReverse transcription

PCRPolymerase chain reaction

BLIBioluminescent imaging

SSBSingle-strand break

NHEJNonhomologous end joining

Na Young Jang, Dan Hyo Kim and Bong Jun Cho contributed equally to this work.

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Autor: Na Young Jang - Dan Hyo Kim - Bong Jun Cho - Eun Jung Choi - Jong-Soo Lee - Hong-Gyun Wu - Eui Kyu Chie - In Ah Kim


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