TK216 targets microtubules in Ewing sarcoma cells

Povedano, Juan Manuel; Li, Vicky; Lake, Katherine E.; Bai, Xueliang; Rallabandi, Rameshu; Kim, Jiwoong; Xie, Yang; Brabander, Jef K. De; McFadden, David G.

doi:10.1016/j.chembiol.2022.06.002

Cited by 24 publications

(15 citation statements)

References 34 publications

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“…5 ). This cluster is also comprised of various microtubule destabilizers (e.g., Vincristine, Vinblastine, Vinorelbine) in addition to an inhibitor of RNA helicase A (YK-4-279), which has also been reported to act as a microtubule destabiliser 58 , and kinesin proteins (Eg5_9814), which are important regulators of microtubule dynamics and cell division processes 59 (Fig. 5 d,e, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Multi-omics investigation reveals functional specialization of transcriptional cyclin dependent kinases in cancer biology

Donovan

Galbraith

Espinosa

2022

Sci Rep

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Transcriptional addiction is recognized as a valid therapeutic target in cancer, whereby the dependency of cancer cells on oncogenic transcriptional regulators may be pharmacologically exploited. However, a comprehensive understanding of the key factors within the transcriptional machinery that might afford a useful therapeutic window remains elusive. Herein, we present a cross-omics investigation into the functional specialization of the transcriptional cyclin dependent kinases (tCDKs) through analysis of high-content genetic dependency, gene expression, patient survival, and drug response datasets. This analysis revealed specialization among tCDKs in terms of contributions to cancer cell fitness, clinical prognosis, and interaction with oncogenic signaling pathways. CDK7 and CDK9 stand out as the most relevant targets, albeit through distinct mechanisms of oncogenicity and context-dependent contributions to cancer survival and drug sensitivity. Genetic ablation of CDK9, but not CDK7, mimics the effect on cell viability the loss of key components of the transcriptional machinery. Pathway analysis of genetic co-dependency and drug sensitivity data show CDK7 and CDK9 have distinct relationships with major oncogenic signatures, including MYC and E2F targets, oxidative phosphorylation, and the unfolded protein response. Altogether, these results inform the improved design of therapeutic strategies targeting tCDKs in cancer.

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Section: Resultsmentioning

confidence: 99%

Multi-omics investigation reveals functional specialization of transcriptional cyclin dependent kinases in cancer biology

Donovan

Galbraith

Espinosa

2022

Sci Rep

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“…Studies of epigenetic agents have become an important research focus as this is another tumor regulatory mechanism in tumor pathogenesis. However, the e cacy of EZH2 was subtle in clinical trials of its use in other sarcomas, especially when used as a single-agent therapy [31,32]. In ES, we found an ORR of 15% in the modi ed intention-to-treat analysis, with durable responses and a median progression-free survival of 5.5 months [3].…”

Section: Discussionmentioning

confidence: 76%

A potential alternative systemic treatment option for epithelioid sarcoma

Xie

Liang

et al. 2022

Preprint

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Background: Epithelioid sarcoma is a rare soft tissue sarcoma characterized by SMARCB1/INI1 deficiency. Much attention has been paid to the selective EZH2 inhibitor tazemetostat, where other systemic treatments are generally ignored. To explore alternative treatment options, we studied the effects of irinotecan-based chemotherapy in a series of epithelioid sarcoma patients. Methods: We retrospectively reviewed data from patients with metastatic or unresectable epithelioid sarcoma at the Peking University People’s Hospital treated with irinotecan (50 mg/m2/d d1-5 Q3W) in combination with Anlotinib (12 mg Qd, 2 weeks on and 1 week off) from July 2015 to November 2021. Results: A total of 54 courses were administered. With a median follow up of 21.2 months (95% CI, 12.2, 68.1), the 5-year overall survival rate was 83.3%. Five of eight (62.5%) patients presented with unresectable localized lesions, including local tumor thrombosis and lymphatic metastasis. The other patients had unresectable pulmonary metastases. Six of eight (75%) patients had progressed following two lines of systemic therapy. The objective response rate reached 37.5% (three of eight patients) while stabilized disease was observed in 62.5% (five of eight) of patients. No patient had progressed at initial evaluation. At the last follow up, two patients were still using the combination and three patients had ceased the therapy due to toxicities such as diarrhea, nausea, and emesis. One patient changed to tazemetostat for maintenance and one patient stopped treatment due to coronavirus disease 2019 (COVID-19). Another patient stopped therapy as residual lesions had been radiated. Conclusions: The combination of irinotecan and Anlotinib as a salvage regimen may be considered another effective treatment option for refractory epithelioid sarcoma. Trial registration: This trial was approved in the Medical Ethics Committee of Peking University People’s Hospital on October 28, 2022 (No.: 2022PHD015-002). The trial was registered in Clinicaltrials.gov with identifier no. NCT05656222.

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“…The importance of rigorous target validation in cells is highlighted by several recent examples where compounds were optimized in vitro and advanced to the clinic but were later found to work through alternative cellular targets. 46,47 For compounds where optimization is guided by an in vitro assay, a correlation between the in vitro and in vivo structure-activity relationship is often utilized to provide evidence for the cellular target. However, confusion may arise if the in vitro assay does not faithfully reproduce the effects of cellular target engagement, or the physicochemical properties of a compound influence activity in either the cell or cell-free assay.…”

Section: Discussionmentioning

confidence: 99%

Inducible mismatch repair streamlines forward genetic approaches to target identification of cytotoxic small molecules

Nguyen

Fang

Kim

et al. 2023

Preprint

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Orphan cytotoxins are small molecules for which the mechanism of action (MoA) is either unknown or ambiguous. Unveiling the mechanism of these compounds may lead to useful tools for biological investigation and in some cases, new therapeutic leads. In select cases, the DNA mismatch repair-deficient colorectal cancer cell line, HCT116, has been used as a tool in forward genetic screens to identify compound-resistant mutations, which have ultimately led to target identification. To expand the utility of this approach, we engineered cancer cell lines with inducible mismatch repair deficits, thus providing temporal control over mutagenesis. By screening for compound resistance phenotypes in cells with low or high rates of mutagenesis, we increased both the specificity and sensitivity of identifying resistance mutations. Using this inducible mutagenesis system, we implicate targets for multiple orphan cytotoxins, including a natural product and compounds emerging from a high-throughput screen, thus providing a robust tool for future MoA studies.

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TK216 targets microtubules in Ewing sarcoma cells

Cited by 24 publications

References 34 publications

Multi-omics investigation reveals functional specialization of transcriptional cyclin dependent kinases in cancer biology

Multi-omics investigation reveals functional specialization of transcriptional cyclin dependent kinases in cancer biology

A potential alternative systemic treatment option for epithelioid sarcoma

Inducible mismatch repair streamlines forward genetic approaches to target identification of cytotoxic small molecules

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