mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

Acquaviva, Jaime; He, Suqin; Sang, Jim; Smith, Donald L.; Sequeira, Manuel; Zhang, Chaohua; Bates, Richard C.; Proia, David A.

doi:10.1158/1541-7786.mcr-13-0605

Cited by 44 publications

(27 citation statements)

References 34 publications

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“…This concept has been evaluated in many cancers [9][10][11][12][13][14][15][16], including numerous attempts in pre-clinical and clinical breast cancer models [17][18][19][20][21][22][23][24][25][26][27] (reviewed in [28]). …”

Section: Discussionmentioning

confidence: 99%

Ratio of proliferation markers and HSP90 gene expression as a predictor of pathological complete response in breast cancer neoadjuvant chemotherapy

Jarząb

Kowal

Bal

et al. 2017

Folia Histochem Cytobiol.

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Introduction. Prediction of response to preoperative breast cancer chemotherapy may offer a substantial optimization of medical management of this disease. The most efficient prediction would be done a priori, before the start of chemotherapy and based on the biological features of patient and tumor. Numerous markers have been proposed but none of them has been applied as a routine. The role of MKI67 and HSP90 expression has been recently suggested to predict treatment sensitivity in HER2-positive breast cancer. The aim of this study was to validate the utility of proliferation based markers (MKI67 and CDK1) and heat shock proteins (namely HSP90) to predict response to chemotherapy in cohort of breast cancer patients treated preoperatively. Material and methods. Ninety-three patients with breast cancer, all females, mean age 42.2 years, among them 32% T1-T2 patients, 49% T3 patients and 13% with T4 tumor stage, 27% N0, 42% N1, 16% N2, 15% N3 were subjected to initial chemotherapy. The majority of patients (86%) received anthracycline and taxane chemotherapy. Among the patients there were 9 individuals with metastatic disease (M1) at initial presentation, and 11 patients were not treated surgically after initial chemotherapy (no sufficient disease response). From 82 patients operated on, 20 patients (24%) showed pathological complete response (pCR), while in 62 patients there was Results. There were no statistically significant differences in MKI67 and CDK1 expression between pCR and no pCR groups (p = 0.099 and 0.35, respectively), although the median expression of both genes was slightly higher in pCR group. In contrast, both HSP90AA1 and HSP90AB1 transcripts showed decreased expression in pCR group (medians 0.77 and 0.55) when compared to no pCR group (median 0.86 and 0.73), statistically significant for HSP90AA1 (p = 0.031) and of borderline significance for HSP90AB1 (p = 0.054). The most significant predictor of pCR was the ratio of CDK1 transcript to HSP90AA transcript. This ratio was significantly higher in CR group (median 0.99) than in no CR group (median 0.68, p = 0.0023), and showed a potential diagnostic utility (area under receiver operating characteristic [ROC] curve 0.72). Conclusions. HSP90AA1 and AB1 genes exhibit low expression in breast cancers highly sensitive to chemotherapy and may indicate the patients with higher probability of pathological complete response. The ratio of HSP90AA1 to proliferation-related markers (CDK1 or MKI67) may be even better predictor of pCR chance, with higher expression of proliferation genes and lower stress response in patients sensitive to chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Ratio of proliferation markers and HSP90 gene expression as a predictor of pathological complete response in breast cancer neoadjuvant chemotherapy

Jarząb

Kowal

Bal

et al. 2017

Folia Histochem Cytobiol.

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“…be prevented by modest, non-HSF1-activating levels of HSP90 inhibition (16)(17)(18)? As a specific test of this hypothesis, we examined whether levels of HSP90 inhibition that are much lower than those commonly used could restrict the ability of tumors to evolve resistance to hormonal therapy in models of estrogen receptor-positive (ER+) breast cancer.…”

Section: Significancementioning

confidence: 99%

“…Because HSP70 expression is regulated by HSF1, it serves as a surrogate marker for the activation of this factor (16,17). Thus, in practice, at the levels of HSP90 inhibition currently sought in the clinic, the very real benefits that might be achieved through the differential vulnerability of cancer cells are likely to be attenuated by the activation of HSF1.…”

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confidence: 99%

HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models

Whitesell

Santagata

Mendillo

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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111

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The efficacy of hormonal therapies for advanced estrogen receptorpositive breast cancers is limited by the nearly inevitable development of acquired resistance. Efforts to block the emergence of resistance have met with limited success, largely because the mechanisms underlying it are so varied and complex. Here, we investigate a new strategy aimed at the very processes by which cancers evolve resistance. From yeast to vertebrates, heat shock protein 90 (HSP90) plays a unique role among molecular chaperones by promoting the evolution of heritable new traits. It does so by regulating the folding of a diverse portfolio of metastable client proteins, many of which mediate adaptive responses that allow organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs. Guided by our previous work in pathogenic fungi, in which very modest HSP90 inhibition impairs resistance to mechanistically diverse antifungals, we examined the effect of similarly modest HSP90 inhibition on the emergence of resistance to antiestrogens in breast cancer models. Even though this degree of inhibition fell below the threshold for proteotoxic activation of the heat-shock response and had no overt anticancer activity on its own, it dramatically impaired the emergence of resistance to hormone antagonists both in cell culture and in mice. Our findings strongly support the clinical testing of combined hormone antagonist-low-level HSP90 inhibitor regimens in the treatment of metastatic estrogen receptor-positive breast cancer. At a broader level, they also provide promising proof of principle for a generalizable strategy to combat the pervasive problem of rapidly emerging resistance to molecularly targeted therapeutics.estrogen receptor | antiestrogen | drug resistance | tumor progression | tamoxifen D rastically limiting the efficacy of targeted therapeutics, the emergence of drug resistance in advanced cancers remains nearly inevitable. From yeast to vertebrates, the molecular chaperone heat shock protein 90 (HSP90) allows organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs and environmental stressors (1, 2). It does so by regulating the folding of a highly diverse portfolio of metastable client proteins, many mediating adaptive responses (3, 4).However, this role for HSP90 in adaptation is greatly magnified by its ability to promote the evolution of heritable new traits. To buffer the proteome against unexpected environmental challenges, HSP90 is present in large excess under normal circumstances. This buffering capacity allows it to modulate the manifestation of preexisting and newly acquired genetic variation within heterogeneous populations of cells, and even whole organisms, thereby dramatically expanding the range of phenotypes on which selection can act (1, 2, 5-7). As a dramatic, therapeutically relevant example, we have shown that this HSP90 buffer enables fungal pathogens spanning ∼1 billion years of evolution to evolve and maintain resistance to every major a...

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“…Consistent with the role of mTOR signaling in HSF1-mediated transcription, inhibition of the mTOR pathway abrogates nuclear translocation of HSF1 and the induction of HSPs following exposure to Hsp90 inhibitors. (23). Taken together, these studies provide ample evidence to suggest that HSF1-dependent transactivation is regulated by mTOR activity.…”

Section: Hsf1 and Protein Translationmentioning

confidence: 75%

Heat Shock Factor 1 in Protein Homeostasis and Oncogenic Signal Integration

2015

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Heat shock factor 1 (HSF1) is a stress-inducible transcription factor and has been described as a multi-faceted modulator of tumorigenesis. Heat shock, accumulation of misfolded proteins, or malignant transformation promotes the activation and nuclear translocation of HSF1, where it binds to the promoters of heat shock proteins and an array of nonheat shock-regulated proteins to upregulate their transcription. These stress-responsive and tumor-promoting genes in turn alter the ability of tumor cells to respond to a variety of stresses and enable them to thrive in less than favorable growth conditions. Although a direct role for HSF1 in promoting mRNA transcription of tumor-promoting genes has been suggested, it appears that this property is context-and celltype dependent. Furthermore, recent studies have demonstrated a direct involvement of mTOR signaling in regulating HSF1-mediated transcription, thus establishing a direct link between protein translation and HSF1 activity. Interestingly, there is a growing understanding of the signaling pathways that are modulated by HSF1 in a variety of tumor types and the co-option of these survival pathways by HSF1 to promote tumorigenesis. This review will focus on the role of HSF1 in protein homeostasis and HSF1-mediated oncogenic signaling pathways that together promote tumorigenesis. Cancer Res; 75(6); 907-12. Ó2015 AACR.

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mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

Cited by 44 publications

References 34 publications

Ratio of proliferation markers and HSP90 gene expression as a predictor of pathological complete response in breast cancer neoadjuvant chemotherapy

Ratio of proliferation markers and HSP90 gene expression as a predictor of pathological complete response in breast cancer neoadjuvant chemotherapy

HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models

Heat Shock Factor 1 in Protein Homeostasis and Oncogenic Signal Integration

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