Phospho-S6 ribosomal protein: a potential new predictive sarcoma marker for targeted mTOR therapy

Abstract

Metastatic sarcomas are commonly resistant to chemotherapy. The serine/threonine kinase, mammalian target of rapamycin (mTOR), is a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway thought to have a key role in controlling cancer growth and thus is an important target for cancer therapy. Several inhibitors of mTOR are in clinical trials, including AP23573, which is being tested on metastatic sarcomas and other tumors. We hypothesized that a marker for the activity of mTOR, phosphorylated S6 ribosomal protein, would be predictive of clinical response to the drug, that is, high tumor expression would signify better response than low expression. This was a blinded study. Of 26 patients treated, 20 remained on study, with available paraffin blocks. Fourteen patients received AP23573 alone and six patients received AP23573 in combination with adriamycin. An antibody to the phosphorylated S6 ribosomal protein was used to stain the tumors, all high-grade sarcomas. Pretreatment biopsy or resection material was tested: the original tumor (n ¼ 6) or tumor recurrence/metastasis (n ¼ 14); either of these may have been after treatment with other agents. Staining was scored for both quantity/percentage of tumor cells and intensity. Scoring was performed without knowledge of tumor response. Staining quantity could be categorized into two natural groups: high expressors (Z20% of tumor cells, 11 cases) and low expressors (0-10% of tumor cells, 9 cases). The highexpression group had eight stable and three progressive cases (73% stable disease); the low-expression group had three stable and six progressive cases (67% progressive disease). Chi-square analysis showed statistical significance (Pr0.05) at this initial cutoff (10%) selected blindly. The level of phosphorylated S6 ribosomal protein expression was predictive of early tumor response to the mTOR inhibitor, suggesting that this is a promising new predictive sarcoma marker for targeted mTOR inhibitor therapy.

Prognostic significance and function of phosphorylated ribosomal protein S6 in esophageal squamous cell carcinoma

“…In addition, p-S6 expression was predictive of the early sarcoma response to AP23573, an inhibitor of mTOR, 30 suggesting that the status of p-S6 in solid tumors influences the response to anticancer therapy. In this regard, our findings extend the clinical role of p-S6 by demonstrating that elevated p-S6 and an elevated p-S6/S6 ratio are associated with poor clinical outcome of patients with early stage esophagus squamous cell carcinoma.…”

Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

“…10,11 It was originally identified as the target of the antibiotic rapamycin (Rapamune, Wyeth pharmaceuticals, Madison NJ, USA). 12 Subsequent studies revealed a broad spectrum of functions for this molecule, including cell cycle progression, cell proliferation, angiogenesis, and apoptosis.…”

“…19,22,28 Activated mTOR can subsequently phosphorylate p70 S6 kinase-1 (p70 S6K) and 4E-BP. p70 S6K, a serine/threonine kinase, phosphorylates the ribosomal protein S6 of the 40S ribosomal subunit at Ser235 and 236 to increase translation of 5 0 terminal oligopyrimidine tract mRNAs 10 and also binds to mitochondrial membranes and inactivates the pro-apoptotic molecule BAD. 11,20 Phosphorylation of 4E-BP allows assembly of the translational initiation complex with subsequent translation of proteins necessary for progression of the cell cycle past the G1 phase, such as cyclin D1.…”

“…17,21 Alterations in the mTOR pathway are common in numerous malignancies, including prostate cancer, melanoma, malignant glioma, endometrial cancer, renal cell cancer, breast cancer, medulloblastoma, alveolar rhabdomyosarcoma, and mantle cell lymphoma. 10 In general, increased activity of this pathway-either by loss of inhibitory steps or increased activity of growth-promoting elements-can potentially promote tumorigenesis.…”

How Prognostic and Predictive Biomarkers Are Transforming Our Understanding and Management of Advanced Gastric Cancer

“…mTOR activates S6 kinase 1 (S6K1), a kinase involved in protein synthesis, and inhibits the 4-E binding protein (4EBP1), a translational repressor [115] and possible tumor suppressor [116]. There is a suggestion that phosphorylated mTOR expression is a poor prognostic marker because it has been associated with worse disease-free survival in a small cohort [117].…”