Wee1 Kinase Inhibitor AZD1775 Effectively Sensitizes Esophageal Cancer to Radiotherapy

Yang, Linlin; Shen, Changxian; Pettit, Cory; Li, Tianyun; Hu, Andrew; Miller, Eric D.; Zhang, Junran; Lin, Steven H.; Williams, Terence M.

doi:10.1158/1078-0432.ccr-19-3373

Cited by 31 publications

(29 citation statements)

References 65 publications

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“…Experimental evidence has demonstrated that Wee1 inhibitor AZD1775 significantly inhibits cancer growth and impairs RAD51 focus formation in response to radiotherapy 394 . The mechanisms underlying how inhibition of the Wee1 activity by AZD1775, resulting in promotion of the G2/M transition, is to be considered 395 . In this context, cancer cells, which harbor G1 checkpoint aberrations, could enter premature mitosis; ultimately, mitotic catastrophe would occur because of this unsuccessful DDR 388 .…”

Section: Targeting Dna Damage Repair To Sensitize Cancer Cells To Radiationmentioning

confidence: 99%

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Huang

Zhou

2020

Sig Transduct Target Ther

608

457

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Radiotherapy is one of the most common countermeasures for treating a wide range of tumors. However, the radioresistance of cancer cells is still a major limitation for radiotherapy applications. Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers for improving the outcomes of radiotherapy. DNA double-strand breaks are the most lethal lesions induced by ionizing radiation and can trigger a series of cellular DNA damage responses (DDRs), including those helping cells recover from radiation injuries, such as the activation of DNA damage sensing and early transduction pathways, cell cycle arrest, and DNA repair. Obviously, these protective DDRs confer tumor radioresistance. Targeting DDR signaling pathways has become an attractive strategy for overcoming tumor radioresistance, and some important advances and breakthroughs have already been achieved in recent years. On the basis of comprehensively reviewing the DDR signal pathways, we provide an update on the novel and promising druggable targets emerging from DDR pathways that can be exploited for radiosensitization. We further discuss recent advances identified from preclinical studies, current clinical trials, and clinical application of chemical inhibitors targeting key DDR proteins, including DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), ATM/ATR (ataxia-telangiectasia mutated and Rad3-related), the MRN (MRE11-RAD50-NBS1) complex, the PARP (poly[ADP-ribose] polymerase) family, MDC1, Wee1, LIG4 (ligase IV), CDK1, BRCA1 (BRCA1 C terminal), CHK1, and HIF-1 (hypoxia-inducible factor-1). Challenges for ionizing radiation-induced signal transduction and targeted therapy are also discussed based on recent achievements in the biological field of radiotherapy.

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Section: Targeting Dna Damage Repair To Sensitize Cancer Cells To Radiationmentioning

confidence: 99%

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Huang

Zhou

2020

Sig Transduct Target Ther

608

457

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“…Adavosertib potentiates the activity of other DNA damage-inducing agents in preclinical models (10)(11)(12)(13), which has prompted several recent clinical trials (14)(15)(16)(17)(18). Adavosertib also acts as a radiosensitizer, enhancing radiation-induced DNA damage in vivo (19).…”

Section: Introductionmentioning

confidence: 99%

Safety, Antitumor Activity, and Biomarker Analysis in a Phase I Trial of the Once-daily Wee1 Inhibitor Adavosertib (AZD1775) in Patients with Advanced Solid Tumors

Takebe

Naqash

Coyne

et al. 2021

Clinical Cancer Research

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The Wee1 kinase inhibitor adavosertib abrogates cell cycle arrest, leading to cell death. Prior testing of twice-daily adavosertib in patients with advanced solid tumors determined the recommended phase 2 dose (RPh2D). Here, we report results for once-daily adavosertib.Patients and Methods: A 3 + 3 dose escalation design was used, with adavosertib given once daily on days 1-5 and 8-12 in 21-day cycles. Molecular biomarkers of Wee1 activity, including tyrosine 15-phosphorylated Cdk1/2 [pY15-Cdk]), were assessed in paired tumor biopsies.Whole-exome sequencing and RNA sequencing of remaining tumor tissue identified potential predictive biomarkers.Results: Among the 42 patients enrolled, the most common toxicities were gastrointestinal and hematological; dose-limiting toxicities were grade 4 hematological toxicity and grade 3 fatigue.The once-daily RPh2D was 300 mg. Six patients (14%) had confirmed partial responses (PR): 4 ovarian, 2 endometrial. Adavosertib plasma exposures were similar to those from twice-daily dosing. On cycle 1 day 8 (pre-dose), tumor pY15-Cdk levels were higher than baseline in 4 of 8 patients, suggesting target rebound during the day 5-8 dosing break. One patient who progressed rapidly had a tumor WEE1 mutation and potentially compensatory PKMYT1 overexpression.Baseline CCNE1 overexpression occurred in both of 2 responding patients, only 1 of whom had CCNE1 amplification, and in 0 of 3 non-responding patients. Conclusions:We determined the once-daily adavosertib RPh2D and observed activity in patients with ovarian or endometrial carcinoma, including 2 with baseline CCNE1 mRNA overexpression. Future studies will determine whether CCNE1 overexpression is a predictive biomarker for adavosertib.

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“…Wee1 has been reported to be highly expressed in numerous malignancies including breast, hepatocellular, lung, melanoma, and others ( 33 ). To assess the role of Wee1, we utilized the Wee1 inhibitor MK-1775 (adavosertib, AZD1775), which has been evaluated in numerous preclinical and clinical trials as single agent or in combination, often with DNA damaging agents ( 41 – 43 ). Notably, recent reports have highlighted synergistic potential for MK-1775 in combination with other kinase inhibitors, including TAK228 ( 34 ) and alisertib ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment

Ye¹,

Sharipova²,

Kozinova³

et al. 2021

JCI Insight

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Management of gastrointestinal stromal tumors (GISTs) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of RTK inhibitors in advanced disease. Stratification of GISTs into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GISTs, resistance remains a significant clinical problem. Development of effective treatment strategies for refractory GISTs requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases essential in GISTs. Using multiplexed inhibitor beads and mass spectrometry, we explored the majority of the kinome in GIST specimens from the 3 most common molecular subtypes ( KIT mutant, PDGFRA mutant, and succinate dehydrogenase deficient) to identify kinase targets. Kinome profiling with loss-of-function assays identified an important role for G 2 /M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT mutant and PDGFRA mutant GIST cell lines as well as notable efficacy of MK-1775 as a monotherapy in the engineered PDGFRA mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

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Wee1 Kinase Inhibitor AZD1775 Effectively Sensitizes Esophageal Cancer to Radiotherapy

Cited by 31 publications

References 65 publications

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Safety, Antitumor Activity, and Biomarker Analysis in a Phase I Trial of the Once-daily Wee1 Inhibitor Adavosertib (AZD1775) in Patients with Advanced Solid Tumors

Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment

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