HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors

Budina-Kolomets, Anna; Webster, Marie R.; Leu, Julia I-Ju; Jennis, Matthew; Krepler, Clemens; Guerrini, Anastasia; Kossenkov, Andrew V.; Xu, Wei; Karakousis, Giorgos C.; Schuchter, Lynn M.; Amaravadi, Ravi K.; Wu, Hong Gyun; Yin, Xiangfan; Liu, Qin; Lu, Yiling; Mills, Gordon B.; Xu, Xaiowei; George, Donna L.; Weeraratna, Ashani T.; Murphy, Maureen E.

doi:10.1158/0008-5472.can-15-2137

Cited by 33 publications

(40 citation statements)

References 42 publications

(53 reference statements)

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“…In vemurafenib-treated SK-MEL-5 cells featuring upregulated EGFR, treatment with erlotinib effectively blocked phosphorylation of EGFR [108]. PET16, an HSP70 inhibitor, synergistically decreased invasion of 1205Lu xenografts injected into the right flank of NOD.Cg- Prkdc scid Il2rg tm1Wjl /SzJ mice when paired with vemurafenib treatment in vivo [188]. …”

Section: Combination Treatments May Effectively Inhibit Melanoma Emtmentioning

confidence: 99%

Potential therapeutic targets of epithelial–mesenchymal transition in melanoma

et al. 2017

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Melanoma is a cutaneous neoplastic growth of melanocytes with great potential to invade and metastasize, especially when not treated early and effectively. Epithelial-mesenchymal transition (EMT) is the process by which melanocytes lose their epithelial characteristics and acquire mesenchymal phenotypes. Mesenchymal protein expression increases the motility, invasiveness, and metastatic potential of melanoma. Many pathways play a role in promotion of mesenchymal protein expression including RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, Wnt/β-catenin, and several others. Downstream effectors of these pathways induce expression of EMT transcription factors including Snail, Slug, Twist, and Zeb that promote repression of epithelial and induction of mesenchymal character. Emerging research has demonstrated that a variety of small molecule inhibitors as well as phytochemicals can influence the progression of EMT and may even reverse the process, inducing re-expression of epithelial markers. Phytochemicals are of particular interest as supplementary treatment options because of their relatively low toxicities and anti-EMT properties. Modulation of EMT signaling pathways using synthetic small molecules and phytochemicals is a potential therapeutic strategy for reducing the aggressive progression of metastatic melanoma. In this review, we discuss the emerging pathways and transcription factor targets that regulate EMT and evaluate potential synthetic small molecules and naturally occurring compounds that may reduce metastatic melanoma progression.

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Section: Combination Treatments May Effectively Inhibit Melanoma Emtmentioning

confidence: 99%

Potential therapeutic targets of epithelial–mesenchymal transition in melanoma

et al. 2017

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“…Hydrogen peroxide (1 μM) was used as a positive control. * Significant versus control untreated cells (p < .001) (Budina-Kolomets et al, 2016;Goloudina, Demidov, & Garrido, 2012).…”

Section: Resultsmentioning

confidence: 93%

“…The Hsp70 protein, often highly expressed in cancer cells, is involved in tumour development and resistance to chemotherapy. It promotes carcinogenesis acting in part as an antiapoptotic factor (Budina‐Kolomets et al, ; Goloudina, Demidov, & Garrido, ). Therefore, a possible relationship between Hsp70 expression and cell death was also investigated.…”

Section: Resultsmentioning

confidence: 99%

“…Some reports show that Hsp70 is overexpressed in melanoma, playing a key role in cancer progression/prognosis and drug resistant (Budina‐Kolomets et al, ). It has been suggested that in melanoma cells, its tumourigenic potential seems to correlate with its ability to disable apoptosis (Budina‐Kolomets et al, ). Therefore, Hsp70 inhibitors show tumour‐selective cytotoxicity, with limited toxicity in normal cells (Budina‐Kolomets et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, Hsp70 inhibitors show tumour‐selective cytotoxicity, with limited toxicity in normal cells (Budina‐Kolomets et al, ). Hsp70 is an obligate cochaperone for Hsp90, and targeting Hsp90 has shown a key role in the treatment of melanoma (Budina‐Kolomets et al, ). It has been hypothesised that combining Hsp70 inhibitors with Hsp90 inhibitors might lead to enhanced efficacy of the latter (Goloudina et al, ; Murphy, ).…”

Section: Discussionmentioning

confidence: 99%

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Isocordoin analogues promote apoptosis in human melanoma cells via Hsp70

Alessandra

Cardile

Avola

et al. 2019

Phytotherapy Research

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Isocordin 1 and a series of 4‐oxyalkyl‐isocordoin analogues 2–8 were evaluated for their cytotoxicity effect against human melanoma cells (A2058). Analogues 4, 5, and 6 showed a higher inhibitory activity with IC50 values of 12.91 ± 0.031, 24.88 ± 0.013, and 11.62 ± 0.017, respectively. These analogues, 4, 5, and 6, also induced an apoptotic response at 12.5‐ and 25‐μM concentrations. They inhibited the expression of antiapoptotic proteins Bcl‐2 and Hsp70, a critical factor that promotes tumour cell survival. In contrast, Bax and caspase‐9 expression, and caspase‐3 enzyme resulted activated. These results were correlated to a DNA fragmentation typical of apoptosis and an increase of intracellular reactive oxygen species (ROS) levels. Alternatively, at higher concentration (50 μM), when the capacity of the cells to sustain Hsp70 synthesis is reduced, our results seem to indicate that necrosis was induced by a further increase in ROS production. Therefore, the central finding in the present study is that these molecules downregulates Hsp70 expression. Altogether, these results suggest that 4‐oxyalkyl‐isocordoin analogues 4, 5, and 6 deserve to be deeply investigated for a possible application as Hsp70 inhibitor in the management of melanoma.

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Using Reverse Phase Protein Array (RPPA) to Identify and Target Adaptive Resistance

Labrie

Fang

Kendsersky

et al. 2019

Advances in Experimental Medicine and Biology

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Tumor cells and the tumor ecosystem rapidly evolve in response to therapy. This tumor evolution results in the rapid emergence of drug resistance that limits the magnitude and duration of response to therapy including chemotherapy, targeted therapy and immunotherapy. Thus, there is an urgent need to understand and interdict tumor evolution to improve patient benefit to therapy. Reverse phase protein arrays (RPPA) provides a powerful tool to evaluate and develop approaches to target the processes underlying one form of tumor evolution: adaptive evolution. Tumor cells and the tumor microenvironment rapidly evolve through rewiring of protein networks to bypass the effects of therapy. In this review, we present the concepts underlying adaptive resistance and use of RPPA in understanding resistance mechanisms and identification of effective drug combinations. We further demonstrate that this novel information is resulting in biomarker driven trials aimed at targeting adaptive resistance and improving patient outcomes.

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HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors

Cited by 33 publications

References 42 publications

Potential therapeutic targets of epithelial–mesenchymal transition in melanoma

Potential therapeutic targets of epithelial–mesenchymal transition in melanoma

Isocordoin analogues promote apoptosis in human melanoma cells via Hsp70

Using Reverse Phase Protein Array (RPPA) to Identify and Target Adaptive Resistance

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