Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer

Viswanathan, Srinivas R.; Nogueira, Marina F.; Buss, Colin G.; Krill-Burger, John M.; Wawer, Mathias; Małolepsza, Edyta; Berger, Ashton C.; Choi, Peter S.; Shih, Juliann; Taylor, Alison M.; Tanenbaum, Benjamin; Pedamallu, Chandra Sekhar; Cherniack, Andrew D.; Tamayo, Pablo; Strathdee, Craig A.; Lage, Kasper; Carr, Steven A.; Schenone, Monica; Bhatia, Sangeeta N.; Vázquez, Francisca; Tsherniak, Aviad; Hahn, William C.; Meyerson, Matthew

doi:10.1038/s41588-018-0155-3

Cited by 58 publications

(57 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We identified many more lethal hits in the screened tumor cell lines than in the primary oral cells. The association of these essential genes with the genetic changes in these tumor cells suggest that collateral lethality does provide a novel strategy to identify vulnerabilities 32 . 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.…”

Section: Discussionmentioning

confidence: 99%

Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

Harten

Boer

Kemp

et al. 2020

Sci Rep

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

Harten

Boer

Kemp

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…The frequencies of LOH at specific loci in common human solid tumors were estimated from ref. 15 . The estimate of eligible patients (EP) per target gene was based on the frequency of heterozygotes (HF) for each SNV in 1000 Genomes, the LOH frequency (LF) and the yearly worldwide incidence (I) of the respective cancer type (Cancer Research UK, 2012), and was calculated as EP = 0.5 × HF × LF × I assuming that only one of the two alleles is an exploitable therapeutic target.…”

Section: Methodsmentioning

confidence: 99%

“…The frequent 1p36 deletion in glioblastoma, entailing loss of ENO1, sensitizes tumor cells to ENO2 inhibition 8 . Similarly, complete losses of POLR2A, MTAP, and ME3 [9][10][11][12] , and partial losses of PSMC2 13 , SF3B1 14 , and MAGOH 15 have been identified as potential therapeutic targets in human cancers. Targeting of the loss of heterozygosity (LOH) events occurring as cancer genomes inactivate tumor suppressor genes has been achieved by allele-specific inhibition, where variants of essential genes such as the 70-kDa subunit of replication protein A (RPA70) near TP53 are silenced using antisense oligonucleotides 16 .…”

mentioning

confidence: 99%

Exploiting loss of heterozygosity for allele-selective colorectal cancer chemotherapy

et al. 2020

View full text Add to dashboard Cite

Cancer chemotherapy targeting frequent loss of heterozygosity events is an attractive concept, since tumor cells may lack enzymatic activities present in normal constitutional cells. To find exploitable targets, we map prevalent genetic polymorphisms to protein structures and identify 45 nsSNVs (non-synonymous small nucleotide variations) near the catalytic sites of 17 enzymes frequently lost in cancer. For proof of concept, we select the gastrointestinal drug metabolic enzyme NAT2 at 8p22, which is frequently lost in colorectal cancers and has a common variant with 10-fold reduced activity. Small molecule screening results in a cytotoxic kinase inhibitor that impairs growth of cells with slow NAT2 and decreases the growth of tumors with slow NAT2 by half as compared to those with wild-type NAT2. Most of the patient-derived CRC cells expressing slow NAT2 also show sensitivity to 6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl)pyrazin-2-amine (APA) treatment. These findings indicate that the therapeutic index of anti-cancer drugs can be altered by bystander mutations affecting drug metabolic genes.

show abstract

“…The genetic or epigenetic events that lead to aneuploidy formation during tumorigenesis, or that allow cancer cells to tolerate it, may also generate unique vulnerabilities in aneuploid cells (compared to their euploid counterparts). While some aneuploidyinduced dependencies would be specific to the altered chromosome 4,[9][10][11][12] , others may be the consequence of more general cellular burdens associated with an abnormal number of chromosomes, independently of specific karyotypes. Indeed, aneuploidy causes various types of cellular stress responses: proteotoxic, metabolic, replicative, mitotic and hypo-osmotic 4,8,13,14 .…”

mentioning

confidence: 99%

Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint

Cohen-Sharir

McFarland

Abdusamad

et al. 2020

Preprint

View full text Add to dashboard Cite

Selective targeting of aneuploid cells is an attractive strategy for cancer treatment. Here, we mapped the aneuploidy landscapes of ~1,000 human cancer cell lines and classified them by their degree of aneuploidy. Next, we performed a comprehensive analysis of large-scale genetic and chemical perturbation screens, in order to compare the cellular vulnerabilities between neardiploid and highly-aneuploid cancer cells. We identified and validated an increased sensitivity of aneuploid cancer cells to genetic perturbation of core components of the spindle assembly checkpoint (SAC), which ensures the proper segregation of chromosomes during mitosis. Surprisingly, we also found highly-aneuploid cancer cells to be less sensitive to short-term exposures to multiple inhibitors of the SAC regulator TTK. To resolve this paradox and to uncover its mechanistic basis, we established isogenic systems of near-diploid cells and their aneuploid derivatives. Using both genetic and chemical inhibition of BUB1B, MAD2 and TTK, we found that the cellular response to SAC inhibition depended on the duration of the assay, as aneuploid cancer cells became increasingly more sensitive to SAC inhibition over time. The increased ability of aneuploid cells to slip from mitotic arrest and to keep dividing in the presence of SAC inhibition was coupled to aberrant spindle geometry and dynamics. This resulted in a higher prevalence of mitotic defects, such as multipolar spindles, micronuclei formation and failed cytokinesis. Therefore, although aneuploid cancer cells can overcome SAC inhibition more readily than diploid cells, the proliferation of the resultant aberrant cells is jeopardized. At the molecular level, analysis of spindle proteins identified a specific mitotic kinesin, KIF18A, whose levels were drastically reduced in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to KIF18A depletion, and KIF18A overexpression restored the sensitivity of aneuploid cancer cells to SAC inhibition. In summary, we identified an increased vulnerability of aneuploid cancer cells to SAC inhibition and explored its cellular and molecular underpinnings. Our results reveal a novel synthetic lethal interaction between aneuploidy and the SAC, which may have direct therapeutic relevance for the clinical application of SAC inhibitors.

show abstract

Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer

Cited by 58 publications

References 63 publications

Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition

Exploiting loss of heterozygosity for allele-selective colorectal cancer chemotherapy

Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint

Contact Info

Product

Resources

About