Expanding roles of cell cycle checkpoint inhibitors in radiation oncology

Hauge, Sissel; Mariampillai, Adrian Eek; Rødland, Gro Elise; Bay, Lilli Theres Eilertsen; Landsverk, Helga B.; Syljuåsen, Randi G.

doi:10.1080/09553002.2021.1913529

Cited by 13 publications

(10 citation statements)

References 113 publications

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Section: Less Synergy Is Observed Between Wee1/atr Inhibitors When Cells Are Co-treated With Radiationmentioning

confidence: 99%

“…Both WEE1 and ATR inhibitors have been shown to radiosensitize cancer cells [28][29][30][31][32][33][34], and are in clinical testing together with ionizing radiation (IR). Radiosensitization is thought to occur through cell cycle checkpoint abrogation, inhibition of DNA repair, and induction of DNA damage in S-phase [32]. To better evaluate the clinical potential of combined WEE1/ATR inhibition, we therefore addressed whether the observed synergy was maintained or possibly enhanced in the presence of additional radiation treatment.…”

Section: Less Synergy Is Observed Between Wee1/atr Inhibitors When Cells Are Co-treated With Radiationmentioning

confidence: 99%

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Differential Effects of Combined ATR/WEE1 Inhibition in Cancer Cells

Rødland

Hauge

Hasvold

et al. 2021

Cancers

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Inhibitors of WEE1 and ATR kinases are considered promising for cancer treatment, either as monotherapy or in combination with chemo- or radiotherapy. Here, we addressed whether simultaneous inhibition of WEE1 and ATR might be advantageous. Effects of the WEE1 inhibitor MK1775 and ATR inhibitor VE822 were investigated in U2OS osteosarcoma cells and in four lung cancer cell lines, H460, A549, H1975, and SW900, with different sensitivities to the WEE1 inhibitor. Despite the differences in cytotoxic effects, the WEE1 inhibitor reduced the inhibitory phosphorylation of CDK, leading to increased CDK activity accompanied by ATR activation in all cell lines. However, combining ATR inhibition with WEE1 inhibition could not fully compensate for cell resistance to the WEE1 inhibitor and reduced cell viability to a variable extent. The decreased cell viability upon the combined treatment correlated with a synergistic induction of DNA damage in S-phase in U2OS cells but not in the lung cancer cells. Moreover, less synergy was found between ATR and WEE1 inhibitors upon co-treatment with radiation, suggesting that single inhibitors may be preferable together with radiotherapy. Altogether, our results support that combining WEE1 and ATR inhibitors may be beneficial for cancer treatment in some cases, but also highlight that the effects vary between cancer cell lines.

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Section: Less Synergy Is Observed Between Wee1/atr Inhibitors When Cells Are Co-treated With Radiationmentioning

confidence: 99%

Section: Less Synergy Is Observed Between Wee1/atr Inhibitors When Cells Are Co-treated With Radiationmentioning

confidence: 99%

Differential Effects of Combined ATR/WEE1 Inhibition in Cancer Cells

Rødland

Hauge

Hasvold

et al. 2021

Cancers

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“…Cell cycle checkpoints constitute another important factor in the response towards irradiation, providing more time for DNA repair before entering S-phase or mitosis in order to avoid mutations and especially mitotic cell death (16). In HNSCC, the majority of HPVpositive and -negative tumors are functionally deficient for p53 and subsequently also for the G1-S cell cycle checkpoint, increasing the dependence on the G2-M checkpoint.…”

Section: Introductionmentioning

confidence: 99%

“…In HNSCC, the majority of HPVpositive and -negative tumors are functionally deficient for p53 and subsequently also for the G1-S cell cycle checkpoint, increasing the dependence on the G2-M checkpoint. Reduction of the radiationinduced G2 arrest can be achieved by inhibition of the ATR/Chk1/ Wee1 axis, as the inhibition of any of these kinases finally counteracts Wee1-mediated inhibitory phosphorylation of cyclin dependent kinase 1 (CDK1), which, in its active state will continue to drive G2-M transition (16,17). Premature mitotic entry and induction of severe replication stress are further therapeutic effects resulting from enhanced CDK1 and CDK2 activity upon inhibition of the ATR/Chk1/Wee1 axis also without irradiation (18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Dual Inhibition of PARP and the Intra-S/G2 Cell Cycle Checkpoints Results in Highly Effective Radiosensitization of HPV-Positive HNSCC Cells

et al. 2021

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In head and neck squamous cell carcinoma (HNSCC), tumors positive for human papillomavirus (HPV) represent a distinct biological entity with favorable prognosis. An enhanced radiation sensitivity of these tumors is evident in the clinic and on the cellular level when comparing HPV-positive and HPV-negative HNSCC cell lines. We could show that the underlying mechanism is a defect in DNA double-strand break repair associated with a profound and sustained G2 arrest. This defect can be exploited by molecular targeting approaches additionally compromising the DNA damage response to further enhance their radiation sensitivity, which may offer new opportunities in the setting of future de-intensified regimes. Against this background, we tested combined targeting of PARP and the DNA damage-induced intra-S/G2 cell cycle checkpoints to achieve effective radiosensitization. Enhancing CDK1/2 activity through the Wee1 inhibitor adavosertib or a combination of Wee1 and Chk1 inhibition resulted in an abrogation of the radiation-induced G2 cell cycle arrest and induction of replication stress as assessed by γH2AX and chromatin-bound RPA levels in S phase cells. Addition of the PARP inhibitor olaparib had little influence on these endpoints, irrespective of checkpoint inhibition. Combined PARP/Wee1 targeting did not result in an enhancement in the absolute number of residual, radiation induced 53BP1 foci as markers of DNA double-strand breaks but it induced a shift in foci numbers from S/G2 to G1 phase cells. Most importantly, while sole checkpoint or PARP inhibition induced moderate radiosensitization, their combination was clearly more effective, while exerting little effect in p53/G1 arrest proficient normal human fibroblasts, thus indicating tumor specificity. We conclude that the combined inhibition of PARP and the intra-S/G2 checkpoint is a highly effective approach for the radiosensitization of HPV-positive HNSCC cells and may represent a viable alternative for the current standard of concomitant cisplatin-based chemotherapy. In vivo studies to further evaluate the translational potential are highly warranted.

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“…Combined treatment with ATRi and radiotherapy is a promising strategy under evaluation in clinical trials ( 10 , 11 , 32 ). While the rationale until recently has been ATR’s function in DNA damage repair and cell cycle checkpoints, a new role for ATR is also emerging in the suppression of antitumor immune responses [reviewed in ( 33 – 35 )]. However, the mechanisms of how ATRi regulate immune effects, and to what extent these are important in human cancers, have been unclear.…”

Section: Discussionmentioning

confidence: 99%

Caspase activation counteracts interferon signaling after G2 checkpoint abrogation by ATR inhibition in irradiated human cancer cells

et al. 2022

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Recent studies suggest that inhibition of the ATR kinase can potentiate radiation-induced antitumor immune responses, but the extent and mechanisms of such responses in human cancers remain scarcely understood. We aimed to assess whether the ATR inhibitors VE822 and AZD6738, by abrogating the G2 checkpoint, increase cGAS-mediated type I IFN response after irradiation in human lung cancer and osteosarcoma cell lines. Supporting that the checkpoint may prevent IFN induction, radiation-induced IFN signaling declined when the G2 checkpoint arrest was prolonged at high radiation doses. G2 checkpoint abrogation after co-treatment with radiation and ATR inhibitors was accompanied by increased radiation-induced IFN signaling in four out of five cell lines tested. Consistent with the hypothesis that the cytosolic DNA sensor cGAS may detect DNA from ruptured micronuclei after G2 checkpoint abrogation, cGAS co-localized with micronuclei, and depletion of cGAS or STING abolished the IFN responses. Contrastingly, one lung cancer cell line showed no increase in IFN signaling despite irradiation and G2 checkpoint abrogation. This cell line showed a higher level of the exonuclease TREX1 than the other cell lines, but TREX1 depletion did not enhance IFN signaling. Rather, addition of a pan-caspase inhibitor restored the IFN response in this cell line and also increased the responses in the other cell lines. These results show that treatment-induced caspase activation can suppress the IFN response after co-treatment with radiation and ATR inhibitors. Caspase activation thus warrants further consideration as a possible predictive marker for lack of IFN signaling.

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Expanding roles of cell cycle checkpoint inhibitors in radiation oncology

Cited by 13 publications

References 113 publications

Differential Effects of Combined ATR/WEE1 Inhibition in Cancer Cells

Differential Effects of Combined ATR/WEE1 Inhibition in Cancer Cells

Dual Inhibition of PARP and the Intra-S/G2 Cell Cycle Checkpoints Results in Highly Effective Radiosensitization of HPV-Positive HNSCC Cells

Caspase activation counteracts interferon signaling after G2 checkpoint abrogation by ATR inhibition in irradiated human cancer cells

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