Oncotarget

Research Papers:

Rapamycin sensitizes cancer cells to growth inhibition by the PARP inhibitor olaparib

Atsushi Osoegawa, Joell J. Gills, Shigeru Kawabata and Phillip A. Dennis _

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Oncotarget. 2017; 8:87044-87053. https://doi.org/10.18632/oncotarget.19667

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Abstract

Atsushi Osoegawa1, Joell J. Gills1, Shigeru Kawabata1 and Phillip A. Dennis1

1Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

Correspondence to:

Phillip A. Dennis, email: [email protected]

Keywords: BRCA mutation, synthetic lethality, DNA damage response, SRB assay, cell cycle

Received: December 31, 2016     Accepted: May 12, 2017     Published: July 28, 2017

ABSTRACT

Poly (ADP-ribose) polymerase inhibitors (PARPi) have been developed and tested in a context of combining it with double-stranded (ds) DNA repair defects or inhibitors, as PARP inhibitor impairs single-stranded (ss) DNA break repair, resulting in the activation of the dsDNA break repair machinery. Rapamycin has been widely prescribed for more than a decade and recent studies have revealed that it may inhibit dsDNA break repair. The combination of the PARP inhibitor olaparib and rapamycin synergistically inhibited cell proliferation in non-small cell lung cancer (NSCLC) cells, and even in triple negative breast cancer (TNBC) cells with BRCA1 mutations. Rad51, which forms a polymer on ssDNA upon dsDNA breaks, plays an essential role in homologous recombination. Olaparib induced Rad51 focus formation, while rapamycin successfully inhibited it both in vivo and in vitro, suggesting that this combination worked through the blocking of both ssDNA break repair and dsDNA break repair; hence the cells cannot go through the G2/M checkpoint. The protein level of PARP was a predictive marker for both PAR activity and Rad51 focus formation in this combination. Collectively, these data suggest that this combination could have therapeutic potential in the treatment of cancer with high PARP expression, or in combination with cytotoxic chemotherapy or radiotherapy.


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