A phase I trial of LY2584702 tosylate, a p70 S6 kinase inhibitor, in patients with advanced solid tumours

Tolcher, Anthony W.; Goldman, Jonathan H.; Patnaik, Amita; Papadopoulos, Kyriakos P.; Westwood, Paul; Kelly, Claudia S.; Bumgardner, William; Sams, Lillian; Geeganage, Sandaruwan; Wang, Tao; Capen, Andrew; Huang, Jianping; Joseph, Sajan; Miller, J. A.; Benhadji, Karim A.; Brail, Les; Rosen, Lee S.

doi:10.1016/j.ejca.2013.11.039

Cited by 55 publications

(50 citation statements)

References 16 publications

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“…S1) in which S6K2 deficient (S6K2 KO) lymphocytes, which developed normally (fig. S1A), were treated with the highly selective S6K1 inhibitor LY2584702 (28) to completely suppress S6K activity (fig. S1B).…”

Section: Resultsmentioning

confidence: 99%

The 4E-BP–eIF4E axis promotes rapamycin-sensitive growth and proliferation in lymphocytes

Lee

Palafox

et al. 2016

Sci. Signal.

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Rapamycin has been used as a clinical immunosuppressant for many years; however, the molecular basis for its selective effects on lymphocytes remains unclear. We investigated the role of two canonical effectors of the mammalian target of rapamycin (mTOR), ribosomal S6 kinases (S6Ks) and eukaryotic initiation factor 4E (eIF4E)–binding proteins (4E-BPs). S6Ks are thought to regulate cell growth (increase in cell size) and 4E-BPs are thought to control proliferation (increase in cell number), with mTORC1 signaling serving to integrate these processes. However, we found that the 4E-BP–eIF4E signaling axis controlled both the growth and proliferation of lymphocytes, processes for which the S6Ks were dispensable. Furthermore, rapamycin disrupted eIF4E function selectively in lymphocytes, which was due to the increased abundance of 4E-BP2 relative to that of 4E-BP1 in these cells and the greater sensitivity of 4E-BP2 to rapamycin. Together, our findings suggest that the 4E-BP–eIF4E axis is uniquely rapamycin-sensitive in lymphocytes, and that this axis promotes clonal expansion of these cells by coordinating growth and proliferation.

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Section: Resultsmentioning

confidence: 99%

The 4E-BP–eIF4E axis promotes rapamycin-sensitive growth and proliferation in lymphocytes

Lee

Palafox

et al. 2016

Sci. Signal.

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“…Rapamycin was used as a positive control to show that the pS6 measurements were completely mTORC1-dependent. We also assessed the contribution of S6K1 to this response using the selective inhibitor LY2584702 (here termed S6K1i) (41). We used S6K1i instead of S6K1 −/− mice because of the reported compensatory upregulation of S6K2 in such mice (30).…”

Section: Resultsmentioning

confidence: 99%

Context-Specific Function of S6K2 in Th Cell Differentiation

Pai

Walsh

Fruman

2016

The Journal of Immunology

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The mammalian target of rapamycin (mTOR) is essential for helper T cell proliferation and effector differentiation, making the mTOR signaling network an attractive immunomodulatory target for autoimmune related diseases. While direct targeting of mTOR-complex-1 (mTORC1) with rapamycin can provide clinical benefit, targeting downstream enzymes has potential to offer more selective immunosuppression. Here we evaluated p70 ribosomal protein S6 Kinase 2 (S6K2), a downstream effector of mTORC1, for its role in T cell function and autoimmunity. S6K2 is a direct substrate of mTORC1, with a potential role in Th17 differentiation suggested by biochemical studies. Using a genetic approach with S6K2 knockout mice, we found that S6K2 loss reduces Th17 skewing and increases Treg differentiation in vitro when cultured in RPMI media. However, S6K2 was dispensable for Th17 differentiation in IMDM media. In an in vivo EAE model in which rapamycin suppresses disease, S6K2 knockout mice did not exhibit differences in clinical score or Th17 differentiation. These results suggest that S6K2 is dispensable for Th17-driven autoimmunity and highlight how distinct experimental conditions can produce significantly different results in T cell differentiation.

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“…PF-4708671 has been used to investigate S6K1 function in glioblastoma survival signaling (Gruber Filbin et al, 2013) and the regulation of pyrimidine biosynthesis (Ben-Sahra et al, 2013; Robitaille et al, 2013). The compound LY-2779964 (LY-2584702 tosylate) was recently described in a single agent Phase I trial in patients with advanced cancers (Tolcher et al, 2014). In parallel, the polykinase inhibitors AD57 and AD80 were shown to inhibit S6K1 and suppress oncogenic function downstream of a transforming mutant of the receptor tyrosine kinase Ret (Dar et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia

et al. 2017

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SUMMARY Genetic S6K1 inactivation can induce apoptosis in PTEN-deficient cells. We analyzed the therapeutic potential of S6K1 inhibitors in PTEN-deficient T cell leukemia and glioblastoma. Results revealed that the S6K1 inhibitor LY-2779964 was relatively ineffective as a single agent, while S6K1-targeting AD80 induced cytotoxicity selectively in PTEN-deficient cells. In vivo, AD80 rescued 50% of mice transplanted with PTEN-deficient leukemia cells. Cells surviving LY-2779964 treatment exhibited inhibitor-induced S6K1 phosphorylation due to increased mTOR-S6K1 co-association, which primed rapid recovery of S6K1 signaling. In contrast, AD80 avoided S6K1 phosphorylation and mTOR co-association, resulting in durable suppression of S6K1-induced signaling and protein synthesis. Kinome analysis revealed that AD80 coordinately inhibits S6K1 together with the TAM family tyrosine kinase AXL. TAM suppression by BMS-777607 or genetic knockdown potentiated cytotoxic responses to LY-2779964 in PTEN-deficient glioblastoma cells. These results reveal that combination targeting of S6K1 and TAMs is a potential strategy for treatment of PTEN-deficient malignancy.

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A phase I trial of LY2584702 tosylate, a p70 S6 kinase inhibitor, in patients with advanced solid tumours

Cited by 55 publications

References 16 publications

The 4E-BP–eIF4E axis promotes rapamycin-sensitive growth and proliferation in lymphocytes

The 4E-BP–eIF4E axis promotes rapamycin-sensitive growth and proliferation in lymphocytes

Context-Specific Function of S6K2 in Th Cell Differentiation

Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia

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