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.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.