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.
Highlights
Triple negative breast cancer (TNBC), lacking the expression of estrogen receptor, progesterone receptor and human EGF receptor-2, represents an especially aggressive and hard to treat subtype
Our previous studies showed that depletion of RAD51 limits metastatic progression of triple negative breast cancer (TNBC) [12], and we suggested that the pressure on the DNA repair pathways induced by the targeting of PARP may force compensation through RAD51 [13], rationalizing targeting RAD51 in this setting
We included PARP1, ATM and CHK1 inhibition, based on our hypothesis that targeting of complementary DNA-damage response (DDR) pathways would be most effective in combination with RAD51 depletion
Summary
Triple negative breast cancer (TNBC), lacking the expression of estrogen receptor, progesterone receptor and human EGF receptor-2, represents an especially aggressive and hard to treat subtype. New targets for TNBC have been proposed to focus on oncogenic lesions and metabolic abnormalities that support the aggressive phenotype [2] These drivers include; oncogene mutation, tumor suppressor loss, mutation or overexpression of DNA repair proteins and enhanced survival via kinase signaling [2]. BRCA-ness creates a shift from HR, which is dysfunctional, towards alternative DNA repair mechanisms, including those regulated by poly(ADP-ribose)polymerases (PARPs) This has provided the rationale for testing PARP inhibitors in TNBC to create synthetic lethality, the mechanism by which the targeting of two genes is lethal, while individually they are not. In search of a novel and rational therapeutic combination for TNBC, several studies identified RAD51 www.impactjournals.com/oncotarget as target in synthetic lethal screens for PARP inhibition in breast cancer [6,7,8,9,10]. We propose that kinome rewiring limits the efficacy of targeting RAD51 and that rational targeted combination therapy is required to achieve effective therapy against TNBC
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