mTOR Inhibition, the Second Generation: ATP-Competitive mTOR Inhibitor Initiates Unexpected Receptor Tyrosine Kinase–Driven Feedback Loop

Keniry, Megan; Parsons, Ramon

doi:10.1158/2159-8290.cd-11-0157

Cited by 10 publications

(7 citation statements)

References 15 publications

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“…Such negative feedback loops have been reported previously to be associated with other kinase inhibitors, including BRAF inhibitors [26] and mTOR inhibitors [22,23]. In this study, our results indicate that although reduction of pERK1/2 levels is significant at an early stage of FGFR inhibition, the downregulation effect is reversed by continuous treatment of two cell lines, KATO III and RT112, with the FGFR inhibitor BGJ398.…”

Section: Discussionsupporting

confidence: 83%

Essential role of AKT in tumor cells addicted to FGFR

Zhang

et al. 2014

Anti-Cancer Drugs

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Tumor cells with genetic amplifications or mutations in the fibroblast growth factor receptor (FGFR) family are often addicted to FGFR and heavily dependent on its signaling to survive. Although it is critical to understand which signaling pathway downstream of FGFR plays an essential role to guide the research and development of FGFR inhibitors, it has remained unclear partly because the tool compounds used in the literature also hit many other kinases, making the results difficult to interpret. With the development of a potent FGFR-specific inhibitor, BGJ398, we are now able to dissect various pathways with low drug concentrations to minimize multiple-target effects. Importantly, here, we show that inhibition of FGFR signaling by BGJ398 leads to only transient inhibition of ERK1/2 phosphorylation, whereas the inhibitory effect on AKT phosphorylation is sustainable, indicating that AKT, not ERK as commonly believed, serves as an appropriate pharmacodynamic biomarker for BGJ398. Although AKT inhibition by a pan-PI3K inhibitor alone has almost no effect on cell growth, heterologous expression of myr-AKT, an active form of AKT, rescues BGJ398-mediated suppression of tumor cell proliferation. These results indicate that AKT is an essential component downstream of FGFR. Finally, combination of the FGFR inhibitor BGJ398 with rapamycin significantly inhibits AKT phosphorylation and enhances their antiproliferative effects in FGFR-addicted cells, suggesting an effective combination strategy for clinical development of FGFR inhibitors.

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Section: Discussionsupporting

confidence: 83%

Essential role of AKT in tumor cells addicted to FGFR

Zhang

et al. 2014

Anti-Cancer Drugs

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“…It has been reported that inhibition of mTORC1 alone or both mTORC1 and mTORC2 leads to activation of EGFR, HER2, HER3, HER4, Insulin receptor and IGF1Rs. 8,10,11,20 Among them, EGFR, HER2, HER3 are well studied and targeted in breast cancer research while the prognostic and therapeutic impact of HER4 expression in breast cancer remains unclear. 21 IRS1 plays a key role in transmitting signals from insulin and IGF1 receptors to intracellular pathways, which is up-regulated by mTOR allosteric inhibitor rapamycin.…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that inhibition of mTORC1 alone or both mTORC1 and mTORC2 leads to activation of EGFR, HER2, HER3, HER4, Insulin receptor and IGF1Rs . Among them, EGFR, HER2, HER3 are well studied and targeted in breast cancer research while the prognostic and therapeutic impact of HER4 expression in breast cancer remains unclear .…”

Section: Resultsmentioning

confidence: 99%

HSP90 inhibitor AUY922 abrogates up‐regulation of RTKs by mTOR inhibitor AZD8055 and potentiates its antiproliferative activity in human breast cancer

Chen

Guo

Shi

et al. 2014

Intl Journal of Cancer

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mTOR inhibition led to activation of upstream receptor tyrosine kinases (RTKs) and AKT, which may attenuate the efficacy of mTOR kinase inhibitors. We sought to discover efficient drug combination with mTOR inhibitors by elucidating the survival feedback loops induced by mTOR inhibition in breast cancer. The feedback signaling upon treatment of mTOR inhibitor AZD8055 was determined and the combinatorial activity of AZD8055 and HSP90 inhibitor AUY922 in cell signaling and proliferation were detected. Treatment of breast cancer T47D cells with AZD8055 induced activation of AKT and phosphatidylinositol 3-kinase (PI3K), which was accompanied with increase in expression of multiple upstream proteins including EGFR, HER2, HER3 and IRS-1. Different RTKs were revealed to be responsible for the reactivation of AKT by AZD8055 in different breast cancer cell lines. Down-regulation of these proteins differentially enhanced the antiproliferative activity of AZD8055. AZD8055 and AUY922 displayed synergistic effect against a panel of human breast cancer cells irrespective their genotype, which was associated with enhanced cell cycle arrest and inhibition of DNA synthesis. AUY922 destabilized multiple tested tyrosine kinases and abrogated activation of AKT induced by AZD8055. AZD8055 also inhibited up-regulation of HSP70 and HSP27 upon AUY922 treatment. Cotreatment of these two drugs demonstrated synergistic activity against triple negative MDA-MB-468 xenograft without enhanced toxicity. The combination of AZD8055 and AUY922 demonstrated synergistic activity against various types of breast cancer and established a mechanistic rationale for a combination approach using catalytic mTOR kinase inhibitor and HSP90 inhibitor in the treatment of breast cancer.

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“…AZD8055, which is an adenosine 5'-triphosphate (ATP)-competitive inhibitor, induces not only better mTORC1 inhibition than rapamycin but also a significant decrease in AKT phosphorylation upon mTORC2 inhibition [ 10 , 11 ]. AZD8055 has been shown to inhibit cell proliferation in several solid tumors [ 12 , 13 ] and to sensitize tumor cells to chemotherapies [ 14 , 15 , 16 ]; however, AZD8055 could also initiate the unexpected activation of phosphatidylinositol 3-kinase (PI3K)/AKT and of certain receptor tyrosine kinases (RTKs), such as HER3 or IGF-1R, in breast cancer or non-small cell lung cancer (NSCLC) cells [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

mTOR Inhibition Induces EGFR Feedback Activation in Association with Its Resistance to Human Pancreatic Cancer

Feng

Zhang

Geng

et al. 2015

IJMS

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The mammalian target of rapamycin (mTOR) is dysregulated in diverse cancers and contributes to tumor progression and drug resistance. The first generation of mTOR inhibitors have failed to show clinical efficiency in treating pancreatic cancers due in part to the feedback relief of the insulin-like growth factor-1 receptor (IGF-1R)-AKT signaling pathway. The second generation of mTOR inhibitors, such as AZD8055, could inhibit AKT activation upon mTOR complex 2 (mTORC2) inhibition. However, whether this generation of mTOR inhibitors can obtain satisfactory activities in pancreatic cancer therapy remains unclear. In this study, we found AZD8055 did not show great improvement compared with everolimus, AZD8055 induced a temporal inhibition of AKT kinase activities and AKT was then rephosphorylated. Additionally, we found that AZD8055-induced transient AKT inhibition increased the expression and activation of epidermal growth factor receptor (EGFR) by releasing its transcriptional factors Fork-head box O 1/3a (FoxO1/3a), which might contribute to cell resistance to AZD8055. The in vitro and in vivo experiments further indicated the combination of AZD8055 and erlotinib synergistically inhibited the mTORC1/C2 signaling pathway, EGFR/AKT feedback activation, and cell growth, as well as suppressed the progression of pancreatic cancer in a xenograft model. This study provides a rationale and strategy for overcoming AZD8055 resistance by a combined treatment with the EGFR inhibitor erlotinib in pancreatic cancer therapy.

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mTOR Inhibition, the Second Generation: ATP-Competitive mTOR Inhibitor Initiates Unexpected Receptor Tyrosine Kinase–Driven Feedback Loop

Cited by 10 publications

References 15 publications

Essential role of AKT in tumor cells addicted to FGFR

Essential role of AKT in tumor cells addicted to FGFR

HSP90 inhibitor AUY922 abrogates up‐regulation of RTKs by mTOR inhibitor AZD8055 and potentiates its antiproliferative activity in human breast cancer

mTOR Inhibition Induces EGFR Feedback Activation in Association with Its Resistance to Human Pancreatic Cancer

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