MTOR inhibition induces compensatory, therapeutically targetable MEK activation in renal cell carcinoma.

Sean T Bailey,Jeffrey S Damrauer,Mingqing Li,Harper L Wilson,Bhavani Krishnan,Bing Zhou,William Y Kim,Jen Jen Yeh,Aleisha M Smith

doi:10.1371/journal.pone.0104413

Sean T Bailey, Jeffrey S Damrauer + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0104413

Copy DOI

Journal: PloS one	Publication Date: Sep 2, 2014
Citations: 26	License type: CC BY 4.0

Affiliation: University of North Carolina at Chapel Hill

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.

Highlights

Recent statistics suggest that there are predicted to be roughly 65,000 new cases and 14,000 deaths in 2013 from renal cell carcinoma (RCC) [1,2]
Our studies investigate the relative efficacy of allosteric versus catalytic mechanistic target of rapamycin (mTOR) inhibition in RCC through both pharmacologic and genetic approaches
We show that as monotherapy, catalytic mTOR inhibition is better at decreasing cellular proliferation and inducing apoptosis than allosteric mTOR inhibition consistent with previous studies in RCC [33]

Summary

Introduction

Recent statistics suggest that there are predicted to be roughly 65,000 new cases and 14,000 deaths in 2013 from renal cell carcinoma (RCC) [1,2]. Clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype of RCC and the vast majority of sporadic ccRCC have inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL). PVHL’s most well understood function is to negatively regulate the hypoxia-inducible factor alpha (HIFa) family of transcription factors (HIF1a, HIF2a, HIF3a) in an oxygen dependent manner via its E3 ubiquitin ligase activity [5,6]. Stabilization of HIFa, either as a consequence of hypoxia or pVHL inactivation leads to transcriptional activation of numerous genes associated with adaptation to a hypoxic environment as well as an unfavorable tumor microenvironment [2,5,10]. While significant tumor responses are seen in the setting of VEGFR inhibition they are much less common upon mTOR inhibition suggesting potential compensatory survival and proliferative mechanisms that can be co-targeted [11,12]

Methods

Results

Conclusion