Mammalian target of rapamycin (mTOR) is a component of a signaling pathway (PTEN/PI3K/AKT) that is frequently dysregulated in cancer. However, its precise relationship to the MAPK cascade (Ras/Raf/MEK/ERK), another pathway often implicated in tumorigenesis, has not been well defined. Recent evidence from tissue specimens obtained from patients who have received mTOR inhibitors suggests that ERK may be activated in response to mTOR interruption. In this issue of the JCI, Waugh Kinkade et al. and Carracedo et al. examine the relationship between these pathways in prostate and breast cancer cell model systems (see the related articles beginning on pages 3051 and 3065, respectively). Their findings suggest a link between inhibition of mTOR and ERK activation, possibly reflecting interruption of a novel negative S6K1-dependent feedback loop. Significantly, both groups observed that simultaneous inhibition of MEK/ERK and mTOR resulted in substantially enhanced antitumor effects both in vitro and in vivo. Together, these findings suggest that concurrent interruption of complementary signaling pathways warrants further investigation in cancer therapy.
Submitter: David Fruman | email@example.com
Authors: Matthew R. Janes, Michael G. Kharas
University of California, Irvine
Published September 4, 2008
Two recent papers in the Journal of Clinical Investigation described the importance of combined targeting of the PI3K/AKT/mTOR and ERK MAPK pathways in cancer (1, 2). One of the rationales behind this strategy was that single targeting of mTOR complex-1 (mTORC1) using rapamycin or the analog RAD001 triggered a feedback loop that increased the activation of ERK, in vitro and in vivo (1). In an accompanying commentary, Steven Grant provided an insightful discussion of the importance of these findings as well as questions for future consideration (3). We would like to comment and expand upon one of these themes.
Dr. Grant writes, “a question arises concerning the optimal strategy to inhibit multicomponent pathways.” He then discusses the observation that in some settings the inhibition of mTORC1 triggers another feedback pathway leading to elevated activity of PI3K and AKT. In a separate recent paper in the Journal of Clinical Investigation, we reported a detailed investigation of the PI3K/AKT/mTOR signaling axis in a mouse model of BCR-ABL+ pre-B acute lymphoblastic leukemia (4). We confirmed the existence of “oncogenic rebound” via rapamycin-induced AKT activation in this cancer model. We also showed that whereas AKT activity requires PI3K function, mTORC1 activity is largely independent of PI3K. To achieve both cell cycle arrest and death of the leukemia cells, it was necessary to inhibit both PI3K and mTORC1. Importantly, there are now small molecules that potently inhibit PI3K as well as mTOR, enzymes that are evolutionarily related. We used one of these compounds, PI-103, as proof-of-concept that dual inhibition of PI3K and mTOR with a single agent suppresses expansion of mouse leukemia cells in vivo and primary human CD34+CD19+ BCR-ABL+ cells in vitro. Another dual PI3K/mTOR inhibitor, BEZ235 (developed by Novartis), is in phase I clinical trials for solid tumors (5). Hence, readers should be aware that targeting multiple nodes in the PI3K/AKT/mTOR pathway with single agents is a promising strategy for effective cancer suppression with surprisingly low toxicity in animals.
We would also like to note that we observed rapamycin-induced elevation in ERK phosphorylation in BCR-ABL+ leukemia cells (4). Furthermore, ERK phosphorylation was elevated in cells lacking PI3K function, and a MEK inhibitor reduced residual S6 kinase activity downstream of mTORC1. Hence, increased ERK activity might compensate for the loss of survival signals in these highly PI3K-addicted cells. These findings underscore the importance of investigating mechanisms that lead to feedback activation of ERK signaling in both solid and hematopoietic malignancies.