Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia

Liu, Hongqi; Feng, Xizhi; Ennis, Kelli; Behrmann, Catherine A.; Sarma, P.N.; Jiang, Tingting; Kofuji, Satoshi; Niu, Liang; Stratton, Yiwen; Thomas, Howard; Yoon, Sang-Oh; Sasaki, Atsuo T.; Plas, David R.

doi:10.1016/j.celrep.2017.02.022

Cited by 21 publications

(20 citation statements)

References 30 publications

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“…However, RET is neither mutated nor expressed in the cancer cell lines used in our study based on published data (37,38). More recently, AD80 has been demonstrated as highly active in lung cancer models containing Kif5B-Ret fusions (39) and also in PTEN-deficient malignancies (40). Our study is the first to demonstrate high activity of AD80 in liver cancer models.…”

Section: Ad80 Induces Transcriptomic Reprograming To a Less Aggressivsupporting

confidence: 56%

Phenotype-Based Screens with Conformation-Specific Inhibitors Reveal p38 Gamma and Delta as Targets for HCC Polypharmacology

Craig

Duffy

et al. 2019

Molecular Cancer Therapeutics

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The approved kinase inhibitors for hepatocellular carcinoma (HCC) are not matched to specific mutations within tumors. This has presented a daunting challenge; without a clear target or mechanism, no straightforward path has existed to guide the development of improved therapies for HCC. Here, we combine phenotypic screens with a class of conformation-specific kinase inhibitors termed type II to identify a multikinase inhibitor, AD80, with antitumoral activity across a variety of HCC preclinical models, including mouse xenografts. Mass spectrometry profiling found a number of kinases as putative targets for AD80, including several receptor and cytoplasmic protein kinases. Among these, we found p38 gamma and delta as direct targets of AD80. Notably, a closely related analog of AD80 lacking p38d/g activity, but retaining several other off-target kinases, lost significant activity in several HCC models. Moreover, forced and sustained MKK6!p38!ATF2 signaling led to a significant reduction of AD80 activity within HCC cell lines. Together with HCC survival data in The Cancer Genome Atlas and RNA-seq analysis, we suggest p38 delta and gamma as therapeutic targets in HCC and an "AD80 inhibition signature" as identifying those patients with best clinical outcomes.

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Section: Ad80 Induces Transcriptomic Reprograming To a Less Aggressivsupporting

confidence: 56%

Phenotype-Based Screens with Conformation-Specific Inhibitors Reveal p38 Gamma and Delta as Targets for HCC Polypharmacology

Craig

Duffy

et al. 2019

Molecular Cancer Therapeutics

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“…Further analysis revealed that sfRon induces AKT-mTORC1-S6K1-S6 signaling, including S6K1 downstream targets such as ribosomal protein S6 and eukaryotic initiation factor 4B (eIF-4B) ( Figure 1B). Previous reports show that S6K1 is a hub for translation control that regulates protein synthesis in dividing cells and enhances cell proliferation [19,20]. In agreement with these findings, we found that sfRon expressing cell lines and PDXs exhibited increased levels of proliferation marker PCNA ( Figure 1B).…”

Section: The Sfron Expression Is Associated With High Activity Of Thesupporting

confidence: 91%

“…Further studies showed that the S6K1 phosphorylation was not accompanied by the increase in phosphorylation of the mTORC1 substrate 4E-BP1 ( Figure 3E). The S6K1 T389 phosphorylation without concomitant activation of mTORC1 downstream targets has been previously describe with other S6K1 inhibitors [20]. However, after drug(s) removal from cells (washout), the cells treated with BMS777607 or BKM120 resumed their signaling to certain extend, while cells treated with AD80 or AD80+BMS777607 had their target-specific signaling completely suppressed ( Figure 3E and Supplementary Table 1).…”

Section: Treatment With Multi-kinase Inhibitor Ad80 Alone or In Combisupporting

confidence: 72%

Multi-kinase targeted therapy as a promising treatment strategy for ovarian tumors expressing sfRon receptor

Wang

Cybula

et al. 2020

Genes Cancer

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The sfRon kinase is an important therapeutic target in ovarian cancer that contributes to prominent tumor growth and disease progression. We reasoned that a multi-kinase inhibition of sfRon pathway might be an effective strategy to achieve a sustained anti-tumor response, while simultaneously preventing treatment resistance. We performed a detailed dissection of sfRon signaling in vitro and demonstrated that S6K1 is a key component of a multi-kinase targeting strategy in sfRon expressing ovarian tumors. We selected AD80 compound that targets several kinases within sfRon pathway including AKT and S6K1, and compared its efficacy with inhibitors that selectively target either sfRon or PI3 kinase. Using human ovarian xenografts and clinically relevant patient-derived xenografts (PDXs), we demonstrated that in vivo treatment with single agent AD80 shows superior efficacy to a standard-care chemotherapy (cisplatin/paclitaxel), or to the direct inhibition of sfRon kinase by BMS777607. Our findings indicate that ovarian tumors expressing sfRon are most effectively treated with multi-kinase inhibitors simultaneously targeting AKT and S6K1, such as AD80, which results in long-term anti-tumor response and prevents metastasis development.

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“…These data also provide important insights into the crosstalk between the mTOR/S6K1 signaling pathway and Myc activation. Several S6K1 inhibitors, such as PF-4708671, LY-2779964 and AD80, have been suggested to be effective in some advanced cancers 52 , 53 . In particular, the compound LY-2779964 has undergone a phase I clinical trial in patients with advanced cancers 54 .…”

Section: Discussionmentioning

confidence: 99%

S6K1 phosphorylation-dependent degradation of Mxi1 by β-Trcp ubiquitin ligase promotes Myc activation and radioresistance in lung cancer

Huang¹,

Hu²,

Zhang³

et al. 2018

Theranostics

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Rationale: Mxi1 is regarded as a potential tumor suppressor protein that antagonizes the transcriptional activity of proto-oncogene Myc. However, the clinical significances and underlying mechanisms by which Mxi1 is regulated in lung cancer remain poorly understood.Methods: Mass spectrometry analysis and immunoprecipitation assay were utilized to detect the protein-protein interaction. The phosphorylation of Mxi1 was evaluated by in vitro kinase assays. Poly-ubiquitination of Mxi1 was examined by in vivo ubiquitination assay. Lung cancer cells stably expressing wild-type Mxi1 or Mxi1-S160A were used for functional analyses. The expression levels of Mxi1 and S6K1 were determined by immunohistochemistry in lung cancer tissues and adjacent normal lung tissues.Results: We found that Mxi1 is downregulated and correlated with poor prognosis in lung cancer. Using tandem affinity purification technology, we provided evidence that β-Trcp E3 ubiquitin ligase interacts with and promotes the ubiquitination and degradation of Mxi1. Furthermore, we demonstrated that Mxi1 is phosphorylated at S160 site by the protein kinase S6K1 and subsequently degraded via the ubiquitin ligase β-Trcp. Moreover, a phosphorylation mutant form of Mxi1 (Mxi1-S160A), which cannot be degraded by S6K1 and β-Trcp, is much more stable and efficient in suppressing the transcriptional activity of Myc and radioresistance in lung cancer cells. More importantly, a strong inverse correlation between S6K1 and Mxi1 expression was observed in human lung cancer tissues.Conclusion: Our findings not only establish a crosstalk between the mTOR/S6K1 signaling pathway and Myc activation, but also suggest that targeting S6K1/Mxi1 pathway is a promising therapeutic strategy for the treatment of lung cancer.

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Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia

Cited by 21 publications

References 30 publications

Phenotype-Based Screens with Conformation-Specific Inhibitors Reveal p38 Gamma and Delta as Targets for HCC Polypharmacology

Phenotype-Based Screens with Conformation-Specific Inhibitors Reveal p38 Gamma and Delta as Targets for HCC Polypharmacology

Multi-kinase targeted therapy as a promising treatment strategy for ovarian tumors expressing sfRon receptor

S6K1 phosphorylation-dependent degradation of Mxi1 by β-Trcp ubiquitin ligase promotes Myc activation and radioresistance in lung cancer

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