Small-Molecule and CRISPR Screening Converge to Reveal Receptor Tyrosine Kinase Dependencies in Pediatric Rhabdoid Tumors

Oberlick, Elaine; Rees, Matthew G.; Seashore‐Ludlow, Brinton; Vázquez, Francisca; Nelson, Geoffrey M.; Dharia, Neekesh V.; Weir, Barbara A.; Tsherniak, Aviad; Ghandi, Mahmoud; Krill-Burger, John M.; Meyers, Robin M.; Montgomery, Phil; Root, David E.; Bieber, Jake M.; Radko, Sandi; Cheah, Jaime H.; Hon, C. Suk-Yee; Shamji, Alykhan F.; Clemons, Paul A.; Park, Peter J.; Dyer, Michael A.; Golub, Todd R.; Stegmaier, Kimberly; Hahn, William C.; Stewart, Elizabeth A.; Schreiber, Stuart L.; Roberts, Charles W.M.

doi:10.1016/j.celrep.2019.07.021

Cited by 32 publications

(24 citation statements)

References 65 publications

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“…In recent years, CRISPR/Cas9 has been widely applied in altering genomes to activate or to repress the expression of genes; thus, its application accelerates the study of the mechanism of tumorigenesis and the development of cancer therapy ( Lee et al, 2019 ). A recent study demonstrated that genome-scale CRISPR/Cas9 gene-knockout screening is applied in discovering potential therapeutic antitumor targets in the cancer cells’ genomes and identified the important role of PTPN11 in pediatric rhabdoid tumors ( Oberlick et al, 2019 ). Genome-scale CRISPR/Cas9 gene-knockout screening can also be applied to study protein function and to explore new therapeutic targets.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Activating Mutation of SHP2 Establishes a Tumorigenic Phonotype Through Cell-Autonomous and Non-Cell-Autonomous Mechanisms

Dong

Han

Meng

et al. 2021

Front. Cell Dev. Biol.

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Gain-of-function mutation of SHP2 is a central regulator in tumorigenesis and cancer progression through cell-autonomous mechanisms. Activating mutation of SHP2 in microenvironment was identified to promote cancerous transformation of hematopoietic stem cell in non-autonomous mechanisms. It is interesting to see whether therapies directed against SHP2 in tumor or microenvironmental cells augment antitumor efficacy. In this review, we summarized different types of gain-of-function SHP2 mutations from a human disease. In general, gain-of-function mutations destroy the auto-inhibition state from wild-type SHP2, leading to consistency activation of SHP2. We illustrated how somatic or germline mutation of SHP2 plays an oncogenic role in tumorigenesis, stemness maintenance, invasion, etc. Moreover, the small-molecule SHP2 inhibitors are considered as a potential strategy for enhancing the efficacy of antitumor immunotherapy and chemotherapy. We also discussed the interconnection between phase separation and activating mutation of SHP2 in drug resistance of antitumor therapy.

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Section: Conclusion and Discussionmentioning

confidence: 99%

Activating Mutation of SHP2 Establishes a Tumorigenic Phonotype Through Cell-Autonomous and Non-Cell-Autonomous Mechanisms

Dong

Han

Meng

et al. 2021

Front. Cell Dev. Biol.

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“…We next aimed to nominate potential targets for pharmacologic inhibition in ATRTs. To first test the coherence of genetic and chemical vulnerabilities in our dataset, we used the Drug Signatures Database (Yoo et al, 2015) to benchmark our screens based on the previously described sensitivity of ATRTs to tyrosine kinase inhibitors (Oberlick et al, 2019;Torchia et al, 2016). Using a set of non-ATRT cell lines previously screened with the Brunello library as a reference (DeWeirdt et al, 2020), we found 16 kinase inhibitor-induced signatures such as that produced by the multi-kinase inhibitor lenvatinib to be significantly enriched (nominal p value < 0.1) in ATRT-specific depleted genes ( Figure S2H).…”

Section: Crispr/cas9 Knockout Screens Reveal Genetic Dependencies Of mentioning

confidence: 99%

Genome-wide CRISPR and small-molecule screens uncover targetable dependencies in ATRT

Merk

Hirsch

Tsiami

et al. 2020

Preprint

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SummaryAtypical teratoid rhabdoid tumors (ATRT) are incurable high-grade pediatric brain tumors. Concepts for molecular-driven therapies in ATRTs lag behind, mainly due to the absence of actionable genetic alterations. We performed genome-wide CRISPR/Cas9 knockout screens in six human ATRT cell lines and identified a total of 671 context-specific essential genes. Based on these genetic dependencies, we constructed a library of small-molecule inhibitors that we found to preferentially inhibit growth of ATRT cells. CDK4/6 inhibitors, among the most potent drugs in our library, are capable of inhibiting tumor growth due to mutual exclusive dependency of ATRTs on CDK4 or CDK6. These distinct dependencies drive heterogeneity in response to CDK4/6 inhibitors in ATRTs. Our approach might serve as a blueprint for fostering the identification of functionally-instructed therapeutic strategies in other incurable diseases beyond ATRT, whose genomic profiles also lack actionable alterations so far.

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“…Genome-scale CRISPR-Cas9 gene-knockout screens alone or in combination with small drug screenings are becoming increasingly employed in the study of pediatric cancers (Aguirre et al, 2016;Oberlick et al, 2019).…”

Section: Crispr/cas9 Technology To Unravel Oncogenic Drivers In Pediatric Soft Tissue Sarcomasmentioning

confidence: 99%

Section: Crispr/cas9 Technology To Unravel Oncogenic Drivers In Pediatric Soft Tissue Sarcomasmentioning

confidence: 99%

“…Through this approach, Oberlick et al discovered a dependency of rhabdoid cells on different receptor tyrosine kinases (RTKs) among which PDGFRA and MET (Oberlick et al, 2019). They demonstrated that these kinases are up-regulated following SMARCB1 loss in cells lines and primary samples providing a proliferative advantage (Oberlick et al, 2019). Stolte et al (2018) used the data of their published CRISPR/Cas9 genome wide screening (Aguirre et al, 2016) to identify among others ES cell lines behaving as p53 wild-type, i.e., dependent on p53, better representing primary ESs genomic status conversely to the available p53m ES cell lines.…”

Section: Crispr/cas9 Technology To Unravel Oncogenic Drivers In Pediatric Soft Tissue Sarcomasmentioning

confidence: 99%

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The CRISP(Y) Future of Pediatric Soft Tissue Sarcomas

Pomella

Rota

2020

Front. Chem.

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The RNA-guided clustered regularly interspaced palindromic repeats (CRISPR)/associated nuclease 9 (Cas9)-based genome editing technology has increasingly become a recognized method for translational research. In oncology, the ease and versatility of CRISPR/Cas9 has made it possible to obtain many results in the identification of new target genes and in unravel mechanisms of resistance to therapy. The majority of the studies have been made on adult tumors so far. In this mini review we present an overview on the major aspects of CRISPR/Cas9 technology with a focus on a group of rare pediatric malignancies, soft tissue sarcomas, on which this approach is having promising results.

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Small-Molecule and CRISPR Screening Converge to Reveal Receptor Tyrosine Kinase Dependencies in Pediatric Rhabdoid Tumors

Cited by 32 publications

References 65 publications

Activating Mutation of SHP2 Establishes a Tumorigenic Phonotype Through Cell-Autonomous and Non-Cell-Autonomous Mechanisms

Activating Mutation of SHP2 Establishes a Tumorigenic Phonotype Through Cell-Autonomous and Non-Cell-Autonomous Mechanisms

Genome-wide CRISPR and small-molecule screens uncover targetable dependencies in ATRT

The CRISP(Y) Future of Pediatric Soft Tissue Sarcomas

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