Senescence is a tumor suppression mechanism defined by stable proliferation arrest. Here we demonstrate that the known synthetic lethal interaction between poly(ADP-ribose) polymerase 1 inhibitors (PARPi) and DNA repair triggers p53-independent ovarian cancer cell senescence defined by senescence-associated phenotypic hallmarks including DNA-SCARS, inflammatory secretome, Bcl-XL-mediated apoptosis resistance, and proliferation restriction via Chk2 and p21 (CDKN1A). The concept of senescence as irreversible remains controversial and here we show that PARPi-senescent cells re-initiate proliferation upon drug withdrawal, potentially explaining the requirement for sustained PARPi therapy in the clinic. Importantly, PARPi-induced senescence renders ovarian and breast cancer cells transiently susceptible to second-phase synthetic lethal approaches targeting the senescence state using senolytic drugs. The combination of PARPi and a senolytic is effective in preclinical models of ovarian and breast cancer suggesting that coupling these synthetic lethalities provides a rational approach to their clinical use and may together be more effective in limiting resistance.

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Advanced prostate cancer (PC) will often progress to a lethal, castration-resistant state. We previously demonstrated that IKKε expression correlated with the aggressiveness of PC disease.Here, we address the potential of IKKε as a therapeutic target in PC. We examined cell fate decisions (proliferation, cell death and senescence) in IKKε-depleted PC-3 cells, which exhibited delayed cell proliferation and a senescent phenotype, but did not undergo cell death. Using IKKε/TBK1 inhibitors, BX795 and Amlexanox, we measured their effects on cell fate decisions in androgen-sensitive-PC and androgen-independent-PC cell lines. Cell cycle analyses revealed a G2/M cell cycle arrest and a higher proportion of cells with 8N DNA content in androgenindependent-PC cells only. Androgen-independent-PC cells also displayed increased senescenceassociated (SA)--galactosidase activity; increased H2AX foci; genomic instability; and altered p15, p16 and p21 expression. In our mouse model, IKK inhibitors also decreased tumor growth of androgen-independent-PC xenografts but not 22Rv1 androgen-sensitive-PC xenografts. Our study suggests that targeting IKK with BX795 or Amlexanox in androgen-independent-PC cells induces a senescence phenotype and demonstrates in vivo anti-tumor activity. These results strengthen the potential of exploiting IKKε as a therapeutic target.