Preclinical validation of a novel compound targeting p70S6 kinase in breast cancer

Abstract

Breast cancer is a frequent and treatable disease. However, when recurrent, breast cancer often becomes refractory to therapy and progresses into metastatic forms that are typically incurable. Thus, understanding and targeting the critical pathways underlying breast cancer recurrence is urgently needed to eradicate primary disease and achieve better prognosis. Recently, we have demonstrated that the ribosomal protein p70S6K is activated in residual breast cancer cells as a result of post-surgical inflammation and that interfering with its activity in the peri-operative setting strongly suppresses recurrence in a mouse model. In order to develop clinically-exploitable treatments targeting p70S6K, we have tested a newly generated compound, called FS-115. FS-115 potently inhibited p70S6K1 (IC50 35nM) with high selectivity over other AGC kinases or PI3K pathway kinases. In vitro, treatment with FS-115 efficiently blocked p70S6K activity in breast cancer cell lines and impaired colony formation and anchorage independent growth. Pharmacokinetic profiling showed that FS-115 exhibited high oral bioavailability, optimal plasma distribution and high brain penetrance. In nude mice, FS-115 strongly suppressed tumor take-rate and primary tumor growth. Oral dosing with FS-115 in a peri-operative schedule was effective in decreasing local recurrence of breast cancer and a long-term treatment schedule was well tolerated and efficiently suppressed distant metastasis formation. Altogether, we propose that FS-115 might be a good candidate for the treatment of breast cancer patients at high risk to relapse.Summary StatementOur results confirm that inhibition of p70S6K represents a valuable opportunity for restraining loco-regional relapse and metastasis in breast cancer and identify in FS-115 a promising candidate-inhibitor to move from preclinical to clinical treatments.

Overproduction of Sch9 leads to its aggregation and cell elongation in Saccharomyces cerevisiae

“…Finally, the constructs we present can be exploited to create superior yeast-based model systems to study processes behind AGC kinase overproduction in cancers. These potential model systems could also be useful for testing novel inhibitors of AGC kinases, for example p70S6K, inhibitors of which are already being developed [ 51 – 53 ].…”

Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells

“…Often components of this and related phospholipid signaling pathways are tumor suppressors [ 124 , 125 ]. Multiple components of the PI3K/PTEN/AKT/mTORC1 pathway have and are being considered for potential targeting in human cancer, e.g., p70S6K in breast cancer [ 126 ], as well as, obesity [ 127 ].…”

Beyond controlling cell size: functional analyses of S6K in tumorigenesis

“…Furthermore, FS-115 potently suppressed the activity of S6K1, exhibiting marked selectivity for kinases from the AGC family. Treatment with FS-115 could also inhibit colony formation and sphere formation of breast cancer cells, suppress primary tumor growth, and reduce distant metastasis of breast cancer in nude mice [ 212 ].…”