Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence

Abstract

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.

Clearance of therapy‐induced senescent tumor cells by the senolytic ABT‐263 via interference with BCL‐XL–BAX interaction

“…Our data indicate that ABT-263 is highly efficient in inducing selective cell death in senescent tumor cells, similar to its action on other non-tumor-senescent cell types [25,38,[56][57][58][59]. Similar to our results, a report by Fleury et al [60] has demonstrated that exposure of p53-mutated ovarian and triple-negative breast tumor cells to the PARP inhibitor, olaparib, results in the induction of reversible senescence. Interestingly, olaparib-induced senescent tumor cells were selectively eliminated by ABT-263 exposure when applied prior to their recovery from senescence.…”

“…Interestingly, olaparib-induced senescent tumor cells were selectively eliminated by ABT-263 exposure when applied prior to their recovery from senescence. The senolytic ability of ABT-263 was also dependent on BCL-X L -mediated resistance to apoptosis [60]. Finally, our data support the premise of the 'two-hit' approach as an effective anticancer strategy [61,62] that may prevent disease recurrence by interfering with the ability of growth-arrested tumors to recover.…”

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

“…Rucaparib increased the accumulation of γH2AX-positive DNA double-stranded breaks induced by low-dose radiation, which manifested as a significant increase in SA-β-gal-positive tumor cells [132]. Interestingly, similar to many observations with CDK inhibitors-induced senescence, senescence induced by PARP inhibition (often in combination with other DNA damaging agents) is associated with a relatively unstable cell cycle arrest, where senescent tumor cells can recover reproductive potential [131,147,148].…”

Targeting RNA Polymerase I transcription synergises with TOP1 inhibition in potentiating the DNA damage response in high-grade serous ovarian cancer

“…agents that selectively kill senescent cells26 or engage anti-tumour immunity via the SASP, which can be further enhanced by agents promoting T cell activation to achieve even more durable responses. Overall, our findings highlight the potential of CX-5461 to enhance salvage therapeutic regimens for treating HGSC patients who have limited effective treatment options.…”