Dual Inhibition of PI3K and mTOR Mitigates Compensatory AKT Activation and Improves Tamoxifen Response in Breast Cancer

Chen, Xiaosong; Zhao, Mengmeng; Hao, Mingang; Sun, Xun; Wang, Jinglong; Mao, Yan Ping; Zu, Lidong; Liu, Junjun; Shen, Yandong; Wang, Jianhua; Shen, Kunwei

doi:10.1158/1541-7786.mcr-13-0212

Cited by 41 publications

(37 citation statements)

References 23 publications

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“…It has been shown that although RAD001 inhibited mTOR downstream activity, it induces p-AKT (Ser473) activation in breast cancer cells. The addition of LY294002 to RAD001 improved the anti-tumor effects and decreased p-AKT (Ser473) activity [31]. The same as this feedback mechanism in our study, RAD001 treatment resulted in AKT activation at 6 h in Calu-1 cell line.…”

Section: Discussionsupporting

confidence: 77%

The comparison between dual inhibition of mTOR with MAPK and PI3K signaling pathways in KRAS mutant NSCLC cell lines

2015

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KRAS mutations are found in 15-25 % of patients with lung adenocarcinoma, and they lead to constitutive activation of KRAS signaling pathway that results in sustained cell proliferation. Currently, there are no direct anti-KRAS therapies available. Therefore, it is rational to target the downstream molecules of KRAS signaling pathway, which are mitogen-activated protein kinase (MAPK) signaling pathway (RAF-MEK-ERK) and PI3K pathway (PI3K-AKT-mTOR). Here, we examined the inhibition of both these pathways alone and in combination and analyzed the anti-proliferative and apoptotic events in KRAS mutant NSCLC cell lines, A549 and Calu-1. Cytotoxicity was determined by MTT assay after the cells were treated with LY294002 (PI3K inhibitor), U0126 (MEK inhibitor), and RAD001 (mTOR inhibitor) for 24 and 48 h. The expression levels of p-ERK, ERK, AKT, p-AKT, p53, cyclinD1, c-myc, p27(kip1), BAX, BIM, and GAPDH were detected by western blot after 6 and 24 h treatment. Although PI3K/mTOR inhibition is more effective in cytotoxicity in A549 and Calu-1 cells, MEK/mTOR inhibition markedly decreases cell proliferation protein marker expressions. Our data show that combined targeting of MEK and PI3K-AKT with mTOR is a better option than single agents alone for KRAS mutant NSCLC, thus opening the possibility of a beneficial treatment strategy in the future.

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Section: Discussionsupporting

confidence: 77%

The comparison between dual inhibition of mTOR with MAPK and PI3K signaling pathways in KRAS mutant NSCLC cell lines

2015

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“…EMT is related to cancer metastasis and IL-6 has been reported to induce EMT by activating JAK-STAT3-SNAIL pathway. 12 In our work, we found that CAFs, through IL-6-mediated activation of both JAK/STAT3 and PI3K/AKT pathways, promoted EMT in MCF7 and T47D cells. These findings suggest that IL-6 from the tumor microenvironment has a critical role in inducing progression of luminal BrCA.…”

Section: Discussionmentioning

confidence: 48%

“…12 Here, we found that the invasive ability of MCF7 and T47D cells was markedly increased when cultured with CAF-CM, but was markedly inhibited by knockdown of IL-6 expression in the CAF (Supplementary Figure 4). These results suggest that secretion of IL-6 by CAFs promotes luminal BrCA invasion.…”

Section: Resultsmentioning

confidence: 77%

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IL-6 secreted by cancer-associated fibroblasts induces tamoxifen resistance in luminal breast cancer

et al. 2014

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Cancer-associated fibroblasts (CAFs) have been implicated in the development of resistance to anticancer drugs; however, the role and mechanism underlying CAFs in luminal breast cancer (BrCA) tamoxifen resistance are unclear. We found that stromal fibroblasts isolated from the central or peripheral area of BrCA have similar CAF phenotype and activity. In vitro and in vivo experiments showed that CAFs derived from clinical-luminal BrCAs induce tamoxifen resistance through decreasing estrogen receptor-α (ER-α) level when cultured with luminal BrCA cell lines MCF7 and T47D. CAFs promoted tamoxifen resistance through interleukin-6 (IL-6) secretion, which activates Janus kinase/signal transducers and activators of transcription (JAK/STAT3) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways in tumor cells, followed by induction of epithelial-mesenchymal transition and upregulation of E3 ubiquitin ligase anaphase-promoting complex 10 activity, which targeted ER-α degradation through the ubiquitin-proteasome pathway. Inhibition of proteasome activity, IL-6 activity or either the JAK/STAT3 or PI3K/AKT pathways markedly reduced CAF-induced tamoxifen resistance. In xenograft experiments of CAFs mixed with MCF7 cells, CAF-specific IL-6 knockdown inhibited tumorigenesis and restored tamoxifen sensitivity. These findings indicate that CAFs mediate tamoxifen resistance through IL-6-induced degradation of ER-α in luminal BrCAs.Oncogene advance online publication, 9 June 2014; doi:10.1038/onc.2014.158.

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“…Moreover, they also disrupt a feedback mechanism that dampens PI3K activity, leading to a compensatory upregulation of Akt activity, causing counterproductive prosurvival effects. On the contrary, the ATP-competitive dual PI3K/mTORC1/2 and mTORC1/2 inhibitors display potent anticancer properties both in vitro and in vivo in a wide range of malignancies, including leukemia (9, 10). Several of these compounds are being tested in preclinical models and they show a consistently robust effect against tumors driven by PI3K/Akt signaling, while they are ineffective against tumors driven by mutations of Ras, which can signal through multiple pathways, such as those for MEK and ERK (11).…”

Section: Introductionmentioning

confidence: 99%

Targeting mTORC1–Mediated Metabolic Addiction Overcomes Fludarabine Resistance in Malignant B Cells

Sharma

Janocha

Hill

et al. 2014

Molecular Cancer Research

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mTORC1 activation occurs frequently in cancers, yet clinical efficacy of rapalogs is limited due to the associated activation of upstream survival pathways. An alternative approach is to inhibit downstream of mTORC1; therefore, acquired resistance to fludarabine (Flu), a purine analog and anti-metabolite chemotherapy, active agent for chronic lymphocytic leukemia (CLL) was investigated. Elevated phospho-p70S6K (T389), an mTORC1 activation marker, predicted Flu resistance in a panel of B-cell lines, isogenic Flu-resistant (FluR) derivatives, and primary human CLL cells. Consistent with the anabolic role of mTORC1, FluR cells had higher rates of glycolysis and oxidative phosphorylation than Flu-sensitive (FluS) cells. Rapalogs (everolimus, rapamycin), induced moderate cell death in FluR and primary CLL cells, and everolimus significantly inhibited glycolysis and oxidative phosphorylation in FluR cells. Strikingly, the higher oxidative phosphorylation in FluR cells was not coupled to higher ATP synthesis. Instead it contributed primarily to an essential, dihydroorotate dehydrogenase (DHODH) catalyzed, step in de novo pyrimidine biosynthesis. mTORC1 promotes pyrimidine biosynthesis by p70S6 kinase-mediated phosphorylation of CAD (Ser1859) and favors S-phase cell cycle progression. We found increased phospho-CAD (S1859) and higher S-phase population in FluR cells. Pharmacological inhibition of de novo pyrimidine biosynthesis using N-phosphonacetyl-L-aspartate (PALA) and leflunomide, RNAi-mediated knockdown of p70S6K, and inhibition of mitochondrial respiration were selectively cytotoxic to FluR, but not FluS cells. These results reveal a novel link between mTORC1-mediated metabolic reprogramming and Flu resistance identifying mitochondrial respiration and de novo pyrimidine biosynthesis as potential therapeutic targets. Implications This study provides the first evidence for mTORC1/p70S6K-dependent regulation of pyrimidine biosynthesis in a relevant disease setting.

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Dual Inhibition of PI3K and mTOR Mitigates Compensatory AKT Activation and Improves Tamoxifen Response in Breast Cancer

Cited by 41 publications

References 23 publications

The comparison between dual inhibition of mTOR with MAPK and PI3K signaling pathways in KRAS mutant NSCLC cell lines

The comparison between dual inhibition of mTOR with MAPK and PI3K signaling pathways in KRAS mutant NSCLC cell lines

IL-6 secreted by cancer-associated fibroblasts induces tamoxifen resistance in luminal breast cancer

Targeting mTORC1–Mediated Metabolic Addiction Overcomes Fludarabine Resistance in Malignant B Cells

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