p70S6 kinase is a critical node that integrates HER-family and PI3 kinase signaling networks

Abstract

Therapies targeting oncogenic drivers rapidly induce compensatory adaptive responses that blunt drug effectiveness, contributing to therapeutic resistance. Adaptive responses are characteristic of robust cell signaling networks, and thus there is increasing interest in drug combinations that co-target the driver and the adaptive response. An alternative approach to co-inhibiting oncogenic and adaptive targets is to identify a critical node where the activities of these targets converge. Nodes of convergence between signaling modules represent potential therapeutic vulnerabilities because their inhibition could result in collapse of the network, leading to enhanced cytotoxicity. In this report we demonstrate that p70S6 kinase (p70S6K) can function as a critical node linking HER-family and phosphoinositide-3-kinase (PI3K) pathway signaling. We used high-throughput combinatorial drug screening to identify adaptive survival responses to targeted therapies, and found that HER-family and PI3K represented compensatory signaling pathways. Co-targeting these pathways with drug combinations caused synergistic cytotoxicity in cases where inhibition of neither target was effective as a monotherapy. We utilized Reverse Phase Protein Arrays and determined that phosphorylation of ribosomal protein S6 was synergistically down-regulated upon HER-family and PI3K/mammalian target of rapamycin (mTOR) co-inhibition. Expression of constitutively active p70S6K protected against apoptosis induced by combined HER-family and PI3K/mTOR inhibition. Direct inhibition of p70S6K with small molecule inhibitors phenocopied HER-family and PI3K/mTOR co-inhibition. These data implicate p70S6K as a critical node in the HER-family/PI3K signaling network. The ability of direct inhibitors of p70S6K to phenocopy co-inhibition of two upstream signaling targets indicates that identification and targeting of critical nodes can overcome adaptive resistance to targeted therapies.

S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts

“…To circumvent this mechanism the RTK/PI3K/mTOR-pathways have been inhibited in various combinations. Axelrod et al (2014) have recently described S6K as a critical node and a potential single target by describing similar responses to S6K1 inhibition alone as to double-targeting RTKs and PI3K/mTOR. We Antibodies showed specific epitope recognition in western blotting.…”

Gossypol sensitizes the antitumor activity of 5-FU through down-regulation of thymidylate synthase in human colon carcinoma cells

“…mTOR kinase can phosphorylate and activate p70S6K1, which is a key mediator of mTOR function and also can regulate diverse cellular processes including protein synthesis, cell growth, and survival [32][33][34]. Inhibiting phosphorylated p70S6K1 suppresses the proliferation and growth of carcinoma and overcomes the adaptive resistance to targeted therapies [35][36][37]. Studies also showed that the inhibition of the mTOR/p70S6K1 signal may be a key molecular event in enhancing 5-FUinduced apoptosis [38].…”

Synergistic apoptosis in head and neck squamous cell carcinoma cells by co‐inhibition of insulin‐like growth factor‐1 receptor signaling and compensatory signaling pathways

“…This knowledge can be applied in 2 ways to negate resistance: (1) blockade of the compensatory pathway should prevent resistance and/or sensitize cells to inhibition of the primary driver, and (2) identification of nodes of convergence between the 2 pathways can provide new targets for therapeutic intervention that may result in more complete and durable responses. 15 Although resistance to combined targeted therapy can occur, it may be less likely to develop when the combination blocks the predicted compensatory pathways, which our drug screen identifies. In the present study, we utilized this combinatorial screening approach to identify drugs that can partner with inhibitors of the IGF-1R/ PI3K/AKT signaling axis to generate synergistic growth inhibition in HNSCC.…”

“…Synergistic interactions are indicative of links between the targeted pathways and thus provide insight into compensatory relationships. This knowledge can be applied in 2 ways to negate resistance: (1) blockade of the compensatory pathway should prevent resistance and/or sensitize cells to inhibition of the primary driver, and (2) identification of nodes of convergence between the 2 pathways can provide new targets for therapeutic intervention that may result in more complete and durable responses . Although resistance to combined targeted therapy can occur, it may be less likely to develop when the combination blocks the predicted compensatory pathways, which our drug screen identifies.…”