Treatment of Triple-Negative Breast Cancer with TORC1/2 Inhibitors Sustains a Drug-Resistant and Notch-Dependent Cancer Stem Cell Population

Bhola, Neil E.; Jansen, Valerie M.; Koch, James P.; Li, Hua; Formisano, Luigi; Williams, Janice A.; Grandis, Jennifer R.; Arteaga, Carlos L.

doi:10.1158/0008-5472.can-15-1640-t

Cited by 91 publications

(75 citation statements)

References 43 publications

(37 reference statements)

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“…Conversely, NOTCH signaling was associated with pluripotency markers (OCT4, NANOG) in the BRCA1 MT/RES cell lines by both PLSDA and NTRACER. This association of NOTCH with OCT4 and NANOG is consistent with previous reports in which signaling in resistant cancer cells was connected with the cancer stem cell phenotype (Bhola et al, ; D'Angelo et al, ; Qiu et al, ; Reya et al, ; Ying et al, ). The association of pluripotency markers (OCT4, NANOG) with BRCA1 MT/RES cells but not BRCA1 WT cells possibly indicates a stem cell phenotype for these cells and that this phenotype may enhance NOTCH activity that contributes to the resistance to Olaparib.…”

Section: Discussionsupporting

confidence: 91%

Systems analysis of dynamic transcription factor activity identifies targets for treatment in Olaparib resistant cancer cells

Decker

Hobson

Zhang

et al. 2017

Biotech & Bioengineering

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The development of resistance to targeted therapeutics is a challenging issue for the treatment of cancer. Cancers that have mutations in BRCA, a DNA repair protein, have been treated with poly (ADP-ribose) polymerase (PARP) inhibitors, which target a second DNA repair mechanism with the aim of inducing synthetic lethality. While these inhibitors have shown promise clinically, the development of resistance can limit their effectiveness as a therapy. This study investigated mechanisms of resistance in BRCA-mutated cancer cells (HCC1937) to Olaparib (AZD2281) using TRACER, a technique for measuring dynamics of transcription factor (TF) activity in living cells. TF activity was monitored in the parental HCC1937 cell line and two distinct resistant cell lines, one with restored wild-type BRCA1 and one with acquired resistance independent of BRCA1 for 48 hours during treatment with Olaparib. Partial least squares discriminant analysis (PLSDA) was used to categorize the three cell types based on TF activity, and network analysis was used to investigate the mechanism of early response to Olaparib in the study cells. NOTCH signaling was identified as a common pathway linked to resistance in both Olaparib-resistant cell types. Western blotting confirmed upregulation of NOTCH protein, and sensitivity to Olaparib was restored through co-treatment with a gamma secretase inhibitor. The identification of NOTCH signaling as a common pathway contributing to PARP inhibitor resistance by TRACER indicates the efficacy of transcription factor dynamics in identifying targets for intervention in treatment-resistant cancer and provides a new method for determining effective strategies for directed chemotherapy.

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Section: Discussionsupporting

confidence: 91%

Systems analysis of dynamic transcription factor activity identifies targets for treatment in Olaparib resistant cancer cells

Decker

Hobson

Zhang

et al. 2017

Biotech & Bioengineering

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“…AMPK is traditionally viewed as a tumour suppressor as mTOR is negatively regulated by AMPK bringing about slower growth, and AMPK is also known to stabilize p53 bringing about cell cycle arrest (57). We did not observe transcriptional changes of Notch1 through mTOR that has been previously described (25). While p53 is known to positively regulate Notch1 in epithelial cells (58), we have tested our signalling axis in p53 mutant cell line (MDA-MB-231) indicating that p53 does not play a role in mediating the effects of AMPK on cleaved Notch1.…”

Section: Discussionsupporting

confidence: 50%

“…However, we failed to find a change in the expression of Notch-ligands under AMPK activation (Supplementary Figure 3A). Since mTOR has been associated with both positive (24) and negative (25) regulation of Notch full length receptor and transcript levels respectively, and AMPK activation leads to mTOR inhibition (20, 26), we next gauged the involvement of mTOR in the regulation of cleaved Notch1. Addition of rapamycin, an inhibitor of mTOR, failed to rescue the AMPK inhibition-mediated reduction in cleaved Notch levels (Supplementary Figure 3B), suggesting possible mTOR-independent mechanisms of regulation of cleaved Notch1 levels downstream of AMPK activation.…”

Section: Resultsmentioning

confidence: 99%

AMPK-Fyn signaling promotes Notch1 stability to potentiate hypoxia-induced breast cancer stemness and drug resistance

Lahiry

Kumar

Hari

et al. 2018

Preprint

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SummaryHypoxia is a hall mark of solid tumor microenvironment and contributes to tumor progression and therapy failure. The developmentally important Notch pathway is implicated in cellular response of cancer cells to hypoxia. Yet, the mechanisms that potentiate Notch signaling under hypoxia are not fully understood. Hypoxia is also a stimulus for AMP-activated protein kinase (AMPK), a major cellular energy sensor. In this study, we investigated if AMPK interacts with the Notch pathway and influences the hypoxia-response of breast cancer cells. Activating AMPK with pharmacological agent or genetic approaches led to an increase in the levels of cleaved Notch1 and elevated Notch signaling in invasive breast cancer cell lines. In contrast, inhibition or depletion of AMPK reduced the amount of cleaved Notch1. Significantly, we show that the hypoxia-induced increase in cleaved Notch1 levels requires AMPK activation. Probing into the mechanism, we demonstrate that AMPK activation impairs the interaction between cleaved Notch1 and its ubiquitin ligase, Itch/AIP4 through the tyrosine kinase Fyn. Under hypoxia, the AMPK-Fyn axis promotes inhibitory phosphorylation of Itch which abrogates its interaction with substrates, thus stabilizing cleaved Notch1 by reducing its ubiquitination and degradation. We further show that inhibition of AMPK alleviates the hypoxia-triggered, Notch-mediated stemness and drug resistance phenotype. Breast cancer patient samples also showed co-expression of hypoxia/AMPK/Notch gene signature. Our work thus establishes AMPK as a key component in the adaptation of breast cancer cells to hypoxia, and proposes therapeutic inhibition of AMPK to mitigate the hypoxia-triggered aggressiveness.

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“…19 described the enrichment of cancer stem cells in TNBC cell lines after treatment with PIK3/mTOR or TORC1/2 inhibitors, it correlates with the worse outcome seen in patients overexpressing DDIT4, mainly in patients with acute myeloid leukemia 19 .…”

Section: Discusionmentioning

confidence: 99%

In silico evaluation of DNA Damage Inducible Transcript 4 gene (DDIT4) as prognostic biomarker in several malignancies

Pinto

Rolfo

Raez

et al. 2017

Sci Rep

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DDIT4 gene encodes a protein whose main action is to inhibit mTOR under stress conditions whilst several in vitro studies indicate that its expression favors cancer progression. We have previously described that DDIT4 expression is an independent prognostic factor for tripe negative breast cancer resistant to neoadjuvant chemotherapy. We herein report that high DDIT4 expression is related to the outcome (recurrence-free survival, time to progression and overall survival) in several cancer types. We performed in silico analysis in online platforms, in pooled datasets from KM Plotter and meta-analysis of individual datasets from SurvExpress. High levels of DDIT4 were significantly associated with a worse prognosis in acute myeloid leukemia, breast cancer, glioblastoma multiforme, colon, skin and lung cancer. Conversely, a high DDIT4 expression was associated with an improved prognostic in gastric cancer. DDIT4 was not associated with the outcome of ovarian cancers. Analysis with data from the Cell Miner Tool in 60 cancer cell lines indicated that although rapamycin activity was correlated with levels of MTOR, it is not influenced by DDIT4 expression. In summary, DDIT4 might serve as a novel prognostic biomarker in several malignancies. DDIT4 activity could be responsible for resistance to mTOR inhibitors and is a potential candidate for the development of targeted therapy.DDIT4 gene (for DNA-damage-inducible transcript 4), also known as REDD1 or RTP801, encodes a protein product that is induced by a variety of stress conditions and whose major function is to inhibit mTORC1 by stabilizing the TSC1-TSC2 inhibitory complex [1][2][3] .Despite inhibition of mTOR pathway is a current strategy in the treatment of cancer, paradoxically, several in vitro and in vivo studies indicate that DDIT4 have a protective role against apoptosis, where a knockdown of this gene lead to increased levels of dexamethasone-induced cell death in murine lymphocytes without effect in glucocorticoid-induced cell death in primary thymocytes 4,5 .A recent study by Celik et al., reported that DDIT4 may be used as a surrogate pharmacodynamic marker of ezrin inhibitors compound activity 6 . Only two previous reports describe the prognostic value of DDIT4. Jia et al. 7 , evaluated DDIT4 protein expression (assessed by immunohistochemistry) in 100 primary ovarian tumors describing that a high DDIT4 expression is related to a shorter disease-free survival (P = 0.020) and overall survival (P = 0.023) 7 . In the other hand, our group screened 449 genes related with triple negative breast cancer aggressiveness and found that a high DDIT4 expression was an independent factor associated with a shorter

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Treatment of Triple-Negative Breast Cancer with TORC1/2 Inhibitors Sustains a Drug-Resistant and Notch-Dependent Cancer Stem Cell Population

Cited by 91 publications

References 43 publications

Systems analysis of dynamic transcription factor activity identifies targets for treatment in Olaparib resistant cancer cells

Systems analysis of dynamic transcription factor activity identifies targets for treatment in Olaparib resistant cancer cells

AMPK-Fyn signaling promotes Notch1 stability to potentiate hypoxia-induced breast cancer stemness and drug resistance

In silico evaluation of DNA Damage Inducible Transcript 4 gene (DDIT4) as prognostic biomarker in several malignancies

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