title: RAD51 inhibition in triple negative breast cancer cells is challenged by compensatory survival signaling and requires rational combination therapy.
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.
authors: Tumor Microenvironment Laboratory, QIMR Berghofer, Herston Rd, Herston QLD 4006, Australia.
authors: Adrian P
authors: AP
authors: Wiegmans
authors: Personalized Medicine Laboratory, QIMR Berghofer, Herston Rd, Herston QLD 4006, Australia.
authors: Mariska
authors: M
authors: Miranda
authors: Tumor Microenvironment Laboratory, QIMR Berghofer, Herston Rd, Herston QLD 4006, Australia.
authors: Shu Wen
authors: SW
authors: Wen
authors: Personalized Medicine Laboratory, QIMR Berghofer, Herston Rd, Herston QLD 4006, Australia.
authors: Fares
authors: F
authors: Al-Ejeh
authors: Tumor Microenvironment Laboratory, QIMR Berghofer, Herston Rd, Herston QLD 4006, Australia.|School of Medicine, University of Queensland, Brisbane, QLD 4072, Australia.
authors: Andreas
authors: A
authors: Möller
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D052999:Quinazolinones / Q000008:administration & dosage / Q000494:pharmacology; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C000602343:(E)-3-benzyl-2-(2-(pyridin-3-yl) vinyl) quinazolin-4(3H)-one; D007093:Imidazoles; D011725:Pyridines; D052999:Quinazolinones; C580958:ralimetinib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D048308:Mitogen-Activated Protein Kinase 14; C495153:RAD51 protein, human; D051135:Rad51 Recombinase
keywords: RAD51; kinome; targeted therapy; triple negative breast cancer; p38MAP kinase