mTOR Inhibition Induces Compensatory, Therapeutically Targetable MEK Activation in Renal Cell Carcinoma

Abstract

Rapamycin derivatives allosterically targeting mTOR are currently FDA approved to treat advanced renal cell carcinoma (RCC), and catalytic inhibitors of mTOR/PI3K are now in clinical trials for treating various solid tumors. We sought to investigate the relative efficacy of allosteric versus catalytic mTOR inhibition, evaluate the crosstalk between the mTOR and MEK/ERK pathways, as well as the therapeutic potential of dual mTOR and MEK inhibition in RCC. Pharmacologic (rapamycin and BEZ235) and genetic manipulation of the mTOR pathway were evaluated by in vitro assays as monotherapy as well as in combination with MEK inhibition (GSK1120212). Catalytic mTOR inhibition with BEZ235 decreased proliferation and increased apoptosis better than allosteric mTOR inhibition with rapamycin. While mTOR inhibition upregulated MEK/ERK signaling, concurrent inhibition of both pathways had enhanced therapeutic efficacy. Finally, primary RCC tumors could be classified into subgroups [(I) MEK activated, (II) Dual MEK and mTOR activated, (III) Not activated, and (IV) mTOR activated] based on their relative activation of the PI3K/mTOR and MEK pathways. Patients with mTOR only activated tumors had the worst prognosis. In summary, dual targeting of the mTOR and MEK pathways in RCC can enhance therapeutic efficacy and primary RCC can be subclassified based on their relative levels of mTOR and MEK activation with potential therapeutic implications.

Synergistic targeted inhibition of MEK and dual PI3K/mTOR diminishes viability and inhibits tumor growth of canine melanoma underscoring its utility as a preclinical model for human mucosal melanoma

“…The RAS/ERK and the PI3K/AKT/mTOR pathways are known to intersect with variable feedback and regulatory influences overlapping downstream (Ersahin et al., ; Mendoza et al., ; Shi et al., ; Van Dort et al., ). For example, mTOR inhibition has been shown to result in reciprocal increase in p‐ERK in human cancer (Bailey et al., ; Carracedo et al., ; Zhu et al., ). Corresponding findings in the current study revealed coordinate increased ERK activation in canine MM cell lines upon mTOR inhibition by the dual PI3K/mTOR inhibitor NVP‐BEZ235 in vitro.…”

“…The RAS/ERK and the PI3K/AKT/mTOR pathways are known to intersect with variable feedback and regulatory influences overlapping downstream (Ersahin et al, 2015;Mendoza et al, 2011;Shi et al, 2011;Van Dort et al, 2015). For example, mTOR inhibition has been shown to result in reciprocal increase in p-ERK in human cancer (Bailey et al, 2014;Carracedo et al, 2008;Zhu et al, 2015).…”

The epidermal growth factor receptor pathway in chronic kidney diseases

“…Monoclonal antibodies, such as tras tuzumab, cetuximab and panitumumab, can either block the interaction between the receptor and its ligand or prevent receptor dimerization 86 . In addition to the three known intervention strategies, targeting downstream mediators might also be a potential option for treat ment, such as inhibition of mTOR, an activator of the downstream PI3K signalling pathway 87 .…”

Synergistic roles of p53 and HIF1α in human renal cell carcinoma-cell apoptosis responding to the inhibition of mTOR and MDM2 signaling pathways

“…Blocking mTOR signaling activity by rapamycin and its derivatives, which are serine/threonine kinase inhibitors, has been revealed to inhibit tumor-cell growth and induce cancer-cell apoptosis in various cancers, including RCC. 9 , 16 , 17 Two rapamycin derivatives – RAD001 and CCI-779 – have demonstrated promising antitumor activity with relatively minor toxicity in early clinical trials in advanced cancer patients. 18 – 20 Notably, CCI-779 has been examined as a single agent in RCC, although with a low response rate (7%).…”