Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy

Fang, Yong; McGrail, Daniel J.; Sun, Chaoyang; Labrie, Marilyne; Chen, Xiaohua; Zhang, Dong; Zhang, Ju; Vellano, Christopher P.; Lu, Yiling; Li, Yongsheng; Jeong, Kang Jin; Ding, Zhiyong; Liang, Jiyong; Wang, Steven W.; Dai, Hui; Lee, Sanghoon; Sahni, Nidhi; Mercado‐Uribe, Imelda; Kim, Tae Beom; Chen, Ken; Lin, Shiaw Yih; Peng, Guang; Westin, Shannon N.; Liu, Jinsong; O’Connor, Mark J.; Yap, Timothy A.; Mills, Gordon B.

doi:10.1016/j.ccell.2019.05.001

Cited by 156 publications

(162 citation statements)

References 63 publications

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“…Inhibition of the S/G2 checkpoint kinases ATR and CHK1 results in unscheduled replication origin firing, exhausts nuclear RPA pools due to excess ssDNA, depletes dNTPs, and allows mitotic entry in the presence of underreplicated DNA and unrepaired DNA damage from interphase (Toledo et al 2017;Lecona and Fernandez-Capetillo 2018). The combination of PARP inhibitors and ATR or CHK1 inhibitors in HR-deficient cells causes the release of the G2/M arrested cells, accumulation of chromosomal breaks, and aberrations in mitosis followed by cell death Fang et al 2019b). Chromosomal breaks in mitosis, indicative of unrepaired DSBs, are more pronounced for the PARP-ATR inhibitor combination, which is also more effective in inducing tumor regression in ovarian cancer PDX models .…”

Section: Cell Cycle Checkpoint Inhibitorsmentioning

confidence: 99%

“…Furthermore, PARP inhibitors were successfully combined with WEE1 kinase inhibitors (Lallo et al 2018;Parsels et al 2018;Fang et al 2019b). WEE1 kinase regulates S phase and G2/M progression by inhibiting cell cycle-dependent kinases CDK1 and CDK2.…”

Section: Cell Cycle Checkpoint Inhibitorsmentioning

confidence: 99%

“…The combination of PARP and WEE1 inhibitors abrogates G2 arrest and induces mitotic catastrophe, yielding promising results in small cell lung cancer (Lallo et al 2018), KRAS mutated nonsmall cell lung cancers (Parsels et al 2018), gastric cancer , and TP53 mutated cancer (Meng et al 2018). Sequential rather than concurrent inhibition of PARP and ATR or WEE1 is preferable in a clinical setting due to lower toxicity while preserving efficacy (Fang et al 2019b).…”

Section: Cell Cycle Checkpoint Inhibitorsmentioning

confidence: 99%

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PARP and PARG inhibitors in cancer treatment

2020

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Oxidative and replication stress underlie genomic instability of cancer cells. Amplifying genomic instability through radiotherapy and chemotherapy has been a powerful but nonselective means of killing cancer cells. Precision medicine has revolutionized cancer therapy by putting forth the concept of selective targeting of cancer cells. Poly(ADP-ribose) polymerase (PARP) inhibitors represent a successful example of precision medicine as the first drugs targeting DNA damage response to have entered the clinic. PARP inhibitors act through synthetic lethality with mutations in DNA repair genes and were approved for the treatment of BRCA mutated ovarian and breast cancer. PARP inhibitors destabilize replication forks through PARP DNA entrapment and induce cell death through replication stress-induced mitotic catastrophe. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exploit and exacerbate replication deficiencies of cancer cells and may complement PARP inhibitors in targeting a broad range of cancer types with different sources of genomic instability. Here I provide an overview of the molecular mechanisms and cellular consequences of PARP and PARG inhibition. I highlight clinical performance of four PARP inhibitors used in cancer therapy (olaparib, rucaparib, niraparib, and talazoparib) and discuss the predictive biomarkers of inhibitor sensitivity, mechanisms of resistance as well as the means of overcoming them through combination therapy.

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Section: Cell Cycle Checkpoint Inhibitorsmentioning

confidence: 99%

Section: Cell Cycle Checkpoint Inhibitorsmentioning

confidence: 99%

Section: Cell Cycle Checkpoint Inhibitorsmentioning

confidence: 99%

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PARP and PARG inhibitors in cancer treatment

2020

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“…WEE1 is a member of the tyrosine kinase family and is a regulatory protein of the G2/M checkpoint to participate in the modulation of cell cycle progression . WEE1 prolongs the G2 phase via controlling the activity of CDK1, thus allowing more time for DNA repair .…”

Section: Discussionmentioning

confidence: 99%

“…WEE1 is a member of the tyrosine kinase family and is a regulatory protein of the G2/M checkpoint to participate in the modulation of cell cycle progression. 39 WEE1 prolongs the G2 phase via controlling the activity of CDK1, thus allowing more time for DNA repair. 40,41 WEE1 is up-regulated in diverse tumors to exert carcinogenic effects, such as in laryngeal squamous cell carcinoma, neuroblastoma, and glioma, implying that WEE1 may be a promising target for cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Quercetin radiosensitizes non‐small cell lung cancer cells through the regulation of miR‐16‐5p/WEE1 axis

et al. 2020

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Background Quercetin, a widely distributed bioflavonoid, plays a role in combating diverse human cancers including non‐small cell lung cancer (NSCLC). However, the role of quercetin in reversing the radioresistance of NSCLC cells and its underlying mechanism are far from being elucidated. Method Radiation‐resistant NSCLC cell lines were established. Quantitative real‐time PCR (qRT‐PCR) was used to detect the expression of miR‐16‐5p and WEE1 G2 checkpoint kinase (WEE1) mRNA in radiation‐resistant cells. After being treated with different concentrations of quercetin and different doses of X‐ray, cell proliferation and apoptosis were monitored by CCK‐8 assay, colony formation assay, and flow cytometry, respectively. Ultimately, the targeting relationship between miR‐16‐5p and WEE1 was verified via a dual fluorescent reporter gene assay. Results The expression of miR‐16‐5p was down‐regulated in radiation‐resistant cells, while the expression of WEE1 was up‐regulated. Quercetin enhanced the radiosensitivity of NSCLC cells in a dose‐ and time‐dependent manner. Furthermore, quercetin treatment increased the expression of miR‐16‐5p and decreased the expression of WEE1. The function of quercetin was reversed by miR‐16‐5p inhibitors or the transfection of WEE1 overexpressing plasmids. Conclusion In conclusion, quercetin enhanced the radiosensitivity of NSCLC cells via modulating the expression of miR‐16‐5p and WEE1.

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Realizing Cancer Precision Medicine by Integrating Systems Biology and Nanomaterial Engineering

et al. 2020

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Many clinical trials for cancer precision medicine have yielded unsatisfactory results due to challenges such as drug resistance and low efficacy. Drug resistance is often caused by the complex compensatory regulation within the biomolecular network in a cancer cell. Recently, systems biological studies have modeled and simulated such complex networks to unravel the hidden mechanisms of drug resistance and identify promising new drug targets or combinatorial or sequential treatments for overcoming resistance to anticancer drugs. However, many of the identified targets or treatments present major difficulties for drug development and clinical application. Nanocarriers represent a path forward for developing therapies with these “undruggable” targets or those that require precise combinatorial or sequential application, for which conventional drug delivery mechanisms are unsuitable. Conversely, a challenge in nanomedicine has been low efficacy due to heterogeneity of cancers in patients. This problem can also be resolved through systems biological approaches by identifying personalized targets for individual patients or promoting the drug responses. Therefore, integration of systems biology and nanomaterial engineering will enable the clinical application of cancer precision medicine to overcome both drug resistance of conventional treatments and low efficacy of nanomedicine due to patient heterogeneity.

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Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy

Cited by 156 publications

References 63 publications

PARP and PARG inhibitors in cancer treatment

PARP and PARG inhibitors in cancer treatment

Quercetin radiosensitizes non‐small cell lung cancer cells through the regulation of miR‐16‐5p/WEE1 axis

Realizing Cancer Precision Medicine by Integrating Systems Biology and Nanomaterial Engineering

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