Oncotarget

Research Papers:

RAD51 inhibition in triple negative breast cancer cells is challenged by compensatory survival signaling and requires rational combination therapy

Adrian P. Wiegmans, Mariska Miranda, Shu Wen Wen, Fares Al-Ejeh and Andreas Möller _

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Oncotarget. 2016; 7:60087-60100. https://doi.org/10.18632/oncotarget.11065

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Abstract

Adrian P. Wiegmans1, Mariska Miranda2, Shu Wen Wen1, Fares Al-Ejeh2,*, Andreas Möller1,3,*

1Tumor Microenvironment Laboratory, QIMR Berghofer, Herston Rd, Herston QLD 4006, Australia

2Personalized Medicine Laboratory, QIMR Berghofer, Herston Rd, Herston QLD 4006, Australia

3School of Medicine, University of Queensland, Brisbane, QLD 4072, Australia

*These authors have contributed equally to this work

Correspondence to:

Andreas Möller, email: Andreas.Moller@qimrberghofer.edu.au

Fares Al-Ejeh, email: Fares.Al-Ejeh@qimrberghofer.edu.au

Keywords: RAD51, kinome, triple negative breast cancer, p38MAP Kinase, targeted therapy

Received: December 01, 2015    Accepted: July 18, 2016    Published: August 05, 2016

ABSTRACT

The molecular rationale to induce synthetic lethality, by targeting defective homologous recombination repair in triple negative breast cancer (TNBC), has proven to have several shortcomings. Not meeting the expected minimal outcomes in clinical trials has highlighted common clinical resistance mechanisms including; increased expression of the target gene PARP1, increased expression or reversion mutation of BRCA1, or up-regulation of the compensatory homologous recombination protein RAD51. Indeed, RAD51 has been demonstrated to be an alternative synthetic lethal target in BRCA1-mutated cancers. To overcome selective pressure on DNA repair pathways, we examined new potential targets within TNBC that demonstrate synthetic lethality in association with RAD51 depletion. We confirmed complementary targets of PARP1/2 and DNA-PK as well as a new synthetic lethality combination with p38. p38 is considered a relevant target in breast cancer, as it has been implicated in resistance to chemotherapy, including tamoxifen. We show that the combination of targeting RAD51 and p38 inhibits cell proliferation both in vitro and in vivo, which was further enhanced by targeting of PARP1. Analysis of the molecular mechanisms revealed that depletion of RAD51 increased ERK1/2 and p38 signaling. Our results highlight a potential compensatory mechanism via p38 that limits DNA targeted therapy.


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