Wee-1 Kinase Inhibition Sensitizes High-Risk HPV+ HNSCC to Apoptosis Accompanied by Downregulation of MCl-1 and XIAP Antiapoptotic Proteins

Tanaka, Noriaki; Patel, Ameeta A.; Wang, Jiping; Frederick, Mitchell J.; Kalu, Nene N.; Zhao, Mei; Fitzgerald, Alison L.; Xie, Tongxin; Silver, Natalie L.; Caulín, Carlos; Zhou, Ge; Skinner, Heath D.; Johnson, Faye M.; Myers, Jeffrey N.; Osman, Abdullah A.

doi:10.1158/1078-0432.ccr-15-0279

Cited by 45 publications

(45 citation statements)

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“…Hence, Wee1 inhibition monotherapy could well serve as chemopreventive strategy to eradicate precancerous changes and prevent cancer and local relapse. Importantly, premalignant cells were comparably sensitive to Wee1 inhibition as the fully transformed HNSCC cancer cell lines and demonstrated comparable mitotic failures [39][40][41] . The chemopreventive potential of Wee1 inhibitors could be investigated in patients with an (erythro-)leukoplakia lesion that harbor genetic changes such as 3p and 9p losses 42 .…”

Section: Discussionmentioning

confidence: 98%

Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

Harten

Boer

Kemp

et al. 2020

Sci Rep

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HPV-negative head and neck squamous cell carcinomas (HNSCCs) develop in precancerous changes in the mucosal lining of the upper-aerodigestive tract. these precancerous cells contain cancerassociated genomic changes and cause primary tumors and local relapses. therapeutic strategies to eradicate these precancerous cells are very limited. Using functional genomic screens, we identified the therapeutic vulnerabilities of premalignant mucosal cells, which are shared with fully malignant HNSCC cells. We screened 319 previously identified tumor-lethal siRNAs on a panel of cancer and precancerous cell lines as well as primary fibroblasts. In total we identified 147 tumor-essential genes including 34 druggable candidates. Of these 34, 13 were also essential in premalignant cells. We investigated the variable molecular basis of the vulnerabilities in tumor and premalignant cell lines and found indications of collateral lethality. Wee1-like kinase (WEE1) was amongst the most promising targets for both tumor and precancerous cells. All four precancerous cell lines were highly sensitive to Wee1 inhibition by Adavosertib (AZD1775), while primary keratinocytes tolerated this inhibitor. Wee1 inhibition caused induction of DNA damage during S-phase followed by mitotic failure in (pre)cancer cells. In conclusion, we uncovered Wee1 inhibition as a promising chemopreventive strategy for precancerous cells, with comparable responses as fully transformed HnScc cells. Head and neck squamous cell carcinomas (HNSCCs) arise in the mucosal lining of the upper-aerodigestive tract and account for around 5% of the total cancer incidence 1,2. The main risk factors for head and neck cancer are smoking and excessive alcohol consumption, infection with a high-risk type of the human papillomavirus (HPV), or genetic predisposition such as Fanconi anemia (FA) 2. FA is characterized by congenital abnormalities, progressing anemia, and cancer predisposition, particularly of oral cancers. These tumors are difficult to manage as FA-patients are sensitive to cross-linking agents such as cisplatin, hampering clinical management of tumors, and for these patients surveillance and prevention is key. Tumors in the head and neck region develop in premalignant mucosal changes, large epithelial areas characterized by cancer-associated genetic changes, also referred to as "fields". These precancerous fields can be centimeters in size, and are often macroscopically invisible. A minority manifests as visible mucosal lesions known as leukoplakia or erythroplakia, which occur with a prevalence of around 0.1-0.2% for leukoplakia 3 , and 0.02-0.2% for erythroplakia 4. Every year, 1-2% of the leukoplakia lesions progress into cancer, and erythroplakia lesions inevitably progress. Despite the occurrence and prevalence of these visible lesions, the large majority of head and neck cancers develop de novo. In resected tumor specimen, however, preceding premalignant changes can be often identified in the surgical margins by either microscopic detection of dysplasia or by ge...

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Section: Discussionmentioning

confidence: 98%

Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

Harten

Boer

Kemp

et al. 2020

Sci Rep

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“…We demonstrated that HNSCC cell lines have wide-ranging sensitivity to these drugs. We focused on the biological effects of PLK1 inhibition on HNSCC cell lines because unlike CHK1/2 [6, 8, 21] and WEE1 [39, 42, 57, 67], the effect of PLK1 inhibition on HNSCC is not well studied, and high expression of PLK1 correlates with poor prognosis for HNSCC [29, 30, 62, 63]. Although both sensitive and resistant cell lines underwent the expected G 2 /M cell-cycle arrest following inhibition or knockdown of PLK1 expression, only the sensitive cell lines underwent substantial apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Treatment with AZD1775 has selectively sensitized HNSCC cell lines to treatment with cisplatin both in vitro and in vivo based on their TP53 mutational statuses via abrogation of cell-cycle arrest at G 2 phase and accumulation of cells harboring unrepaired DNA lesions in during mitosis. Combination therapy of cisplatin and AZD1775 led to aberrant mitosis of HNSCC cells associated with senescence rather than an apoptotic process [39, 42, 57]. …”

Section: Introductionmentioning

confidence: 99%

Mutations of the LIM protein AJUBA mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell-cycle inhibitors

et al. 2017

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The genomic alterations identified in head and neck squamous cell carcinoma (HNSCC) tumors have not resulted in any changes in clinical care, making the development of biomarker-driven targeted therapy for HNSCC a major translational gap in knowledge. To fill this gap, we used 59 molecularly characterized HNSCC cell lines and found that mutations of AJUBA,SMAD4 and RAS predicted sensitivity and resistance to treatment with inhibitors of polo-like kinase 1 (PLK1), checkpoint kinases 1 and 2, and WEE1. Inhibition or knockdown of PLK1 led to cell-cycle arrest at the G2/M transition and apoptosis in sensitive cell lines and decreased tumor growth in an orthotopic AJUBA-mutant HNSCC mouse model. AJUBA protein expression was undetectable in most AJUBA-mutant HNSCC cell lines, and total PLK1 and Bora protein expression were decreased. Exogenous expression of wild-type AJUBA in an AJUBA-mutant cell line partially rescued the phenotype of PLK1 inhibitor-induced apoptosis and decreased PLK1 substrate inhibition, suggesting a threshold effect in which higher drug doses are required to affect PLK1 substrate inhibition. PLK1 inhibition was an effective therapy for HNSCC in vitro and in vivo. However, biomarkers to guide such therapy are lacking. We identified AJUBA, SMAD4 and RAS mutations as potential candidate biomarkers of response of HNSCC to treatment with these mitotic inhibitors.

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“…Both kinases are also critically involved in various processes of the unperturbed cell, especially replication [9,11], and inhibitors of both kinases show single agent antitumor activity [12]. Wee1 was reported to be overexpressed in HPV-positive HNSCC as compared to HPVnegative [13,14] and its inhibition was recently shown to sensitize HPV(+) HNSCC tumor cells toward cisplatin [15]. Here, we investigated the effect of two clinically relevant Chk1 inhibitors http://dx.doi.org/10.1016/j.radonc.2016.11.017 0167-8140/Ó 2016 Elsevier Ireland Ltd. All rights reserved.…”

mentioning

confidence: 99%

G2-checkpoint targeting and radiosensitization of HPV/p16-positive HNSCC cells through the inhibition of Chk1 and Wee1

Busch

Kröger

Jensen

et al. 2017

Radiotherapy and Oncology

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Wee-1 Kinase Inhibition Sensitizes High-Risk HPV+ HNSCC to Apoptosis Accompanied by Downregulation of MCl-1 and XIAP Antiapoptotic Proteins

Cited by 45 publications

References 46 publications

Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

Mutations of the LIM protein AJUBA mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell-cycle inhibitors

G2-checkpoint targeting and radiosensitization of HPV/p16-positive HNSCC cells through the inhibition of Chk1 and Wee1

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