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

Atsushi Osoegawa, Joell Gills, Shigeru Kawabata, Phillip A. Dennis

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)87044-87053
Number of pages10
JournalOncotarget
Volume8
Issue number50
DOIs
StatePublished - 2017

Fingerprint

Sirolimus
DNA Repair
Growth
Triple Negative Breast Neoplasms
Single-Stranded DNA Breaks
Neoplasms
Homologous Recombination
Non-Small Cell Lung Carcinoma
Polymers
Radiotherapy
Cell Proliferation
Drug Therapy
Mutation
DNA
Therapeutics
Poly(ADP-ribose) Polymerase Inhibitors
olaparib
Proteins

Keywords

  • BRCA mutation
  • Cell cycle
  • DNA damage response
  • SRB assay
  • Synthetic lethality

ASJC Scopus subject areas

  • Oncology

Cite this

Rapamycin sensitizes cancer cells to growth inhibition by the PARP inhibitor olaparib. / Osoegawa, Atsushi; Gills, Joell; Kawabata, Shigeru; Dennis, Phillip A.

In: Oncotarget, Vol. 8, No. 50, 2017, p. 87044-87053.

Research output: Contribution to journalArticle

Osoegawa, Atsushi ; Gills, Joell ; Kawabata, Shigeru ; Dennis, Phillip A. / Rapamycin sensitizes cancer cells to growth inhibition by the PARP inhibitor olaparib. In: Oncotarget. 2017 ; Vol. 8, No. 50. pp. 87044-87053.
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