Synthetic essentiality: Targeting tumor suppressor deficiencies in cancer

Zhao, Di; DePinho, Ronald A.

doi:10.1002/bies.201700076

Cited by 25 publications

(22 citation statements)

References 65 publications

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“…Upon the loss of a bona fide tumor suppressor gene through genetic aberrations, a neighboring passenger gene is often homozygously or heterozygously lost as well. These neighboring gene losses were considered futile, but in recent studies it has been demonstrated that the genes located at these loci may play important roles in a variety of key metabolic and regulatory functions, and the subsequent decrease in expression can be exploited as treatment strategy 10,33,34 . Further investigation of collateral lethal hits could lead to the identification of future targets for therapy 32 .…”

Section: Discussionmentioning

confidence: 99%

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: 99%

Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

Harten

Boer

Kemp

et al. 2020

Sci Rep

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“…A similar concept is “collateral lethality,” in which passenger genomic events in tumor cells can create unintended vulnerabilities, particularly in the deletion of redundant essential housekeeping genes . A related concept is “synthetic essentiality,” in which genes that may be deleted in some cancers, are almost always retained in the context of a specific tumor suppressor deficiency, and may represent therapeutic vulnerabilities . Synthetic essential genes may be identified with the aid of available cancer genome and clinical databases, by examining for genes that exhibit mutually exclusive deletion patterns .…”

Section: Synthetic Essentiality: Targeting Genetic Heterogeneity In Pmentioning

confidence: 99%

“…A related concept is “synthetic essentiality,” in which genes that may be deleted in some cancers, are almost always retained in the context of a specific tumor suppressor deficiency, and may represent therapeutic vulnerabilities . Synthetic essential genes may be identified with the aid of available cancer genome and clinical databases, by examining for genes that exhibit mutually exclusive deletion patterns . Zhao et al identified the epigenetic regulator CHD1 as being deleted in some prostate cancers in a mutually exclusive manner with PTEN .…”

Section: Synthetic Essentiality: Targeting Genetic Heterogeneity In Pmentioning

confidence: 99%

Tumor cell heterogeneity and resistance; report from the 2018 Coffey‐Holden Prostate Cancer Academy Meeting

Miyahira

Den²,

Carlo³

et al. 2018

The Prostate

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Introduction The 2018 Coffey‐Holden Prostate Cancer Academy (CHPCA) Meeting, “Tumor Cell Heterogeneity and Resistance,” was held in Los Angeles, California from June 21 to 24, 2018. Methods The CHPCA Meeting is a unique, discussion‐oriented scientific conference convened annually by the Prostate Cancer Foundation (PCF), which focuses on the most critical topics in need of further study to advance the treatment of lethal prostate cancer. The 6th Annual CHPCA Meeting was attended by 70 investigators and concentrated on prostate cancer heterogeneity and treatment resistance. Results The meeting focused on topics including: recognition of tumor heterogeneity, molecular drivers of heterogeneity, the role of the tumor microenvironment, the role of heterogeneity in disease progression, metastasis and treatment resistance, clinical trials designed to target resistance and tumor heterogeneity, and immunotherapeutic approaches to target and overcome tumor heterogeneity. Discussion This review article summarizes the presentations and discussions from the 2018 CHPCA Meeting in order to share this knowledge with the scientific community and encourage new studies that will lead to improved treatments and outcomes for men with prostate cancer.

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“…The rapid realization that there was “addiction” even to non-oncogenic proteins opened up an even larger array of possible targets 24 . The use of large-scale small interfering RNA and short hairpin RNA screens revealed not only gain-of-function mutations that could be therapeutically approached yet also more challenging but, perhaps more interesting, loss-of-function mutations or deletions that are possible synthetic lethality participants 25 , 26 . Some of these synthetic lethality leads fell victim to the common pitfalls that often occur during preclinical cancer target validation, including the well-known off-target effects of small interfering RNA and short hairpin RNA 13 .…”

Section: Empirical Approaches To Discovering Cancer Drug Combination mentioning

confidence: 99%

Cutting down the time to identify challenging tumor therapeutic targets and drug combinations using synthetic lethal approaches

Lazo

2018

F1000Res

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Cancer drug discoverers and developers are blessed and cursed with a plethora of drug targets in the tumor cells themselves and the surrounding stromal elements. This bounty of targets has, at least in part, inspired the rapid increase in the number of clinically available small-molecule, biological, and cellular therapies for solid and hematological malignancies. Among the most challenging questions in cancer therapeutics, especially for small molecules, is how to approach loss-of-function gene mutations or deletions that encode tumor suppressors. A second mounting question is what are the optimal drug combinations. This article will briefly review the recent advances in exploiting in vitro and in vivo synthetic lethal screens to expose cancer pharmacological targets with the goal of developing new drug combinations.

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Synthetic essentiality: Targeting tumor suppressor deficiencies in cancer

Cited by 25 publications

References 65 publications

Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

Tumor cell heterogeneity and resistance; report from the 2018 Coffey‐Holden Prostate Cancer Academy Meeting

Cutting down the time to identify challenging tumor therapeutic targets and drug combinations using synthetic lethal approaches

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