MEK Inhibition Overcomes Cisplatin Resistance Conferred by SOS/MAPK Pathway Activation in Squamous Cell Carcinoma

Kong, Li Ren; Chua, Kian Ngiap; Sim, Wen Jing; Ng, Hsien Chun; Bi, Chonglei; Ho, Jingshan; Nga, Min En; Pang, Yin Huei; Ong, Weijie Richard; Soo, Ross A.; Huynh, Hung; Chng, Wee Joo; Thiery, Jean Paul; Goh, Boon Cher

doi:10.1158/1535-7163.mct-15-0062

Cited by 47 publications

(43 citation statements)

References 48 publications

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“…The primary anticancer mechanism of platinum is to bind covalently to DNA and form platinum-DNA adducts, which results in apoptosis, 30 and apoptosis dysregulation is one of the primary mechanisms underlying cisplatin resistance. 22, 31, 32 In this paper, we reported that BST2 inhibited cisplatin-induced apoptosis in NPC cells and that this effect may be associated with upregulation of anti-apoptotic factors. Specifically, knockdown of BST2 downregulated the anti-apoptotic factors (such as Bcl-X L and livin), whereas overexpression of BST2 upregulated these factors in NPC cells.…”

Section: Discussionmentioning

confidence: 86%

BST2 confers cisplatin resistance via NF-κB signaling in nasopharyngeal cancer

Kuang

Hua

et al. 2017

Cell Death Dis

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Concurrent/adjuvant cisplatin-based chemoradiotherapy is regarded as the standard of treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, patients who do not respond to cisplatin suffer, rather than benefit, from chemotherapy treatment. The goal of this study was to identify molecules involved in cisplatin resistance and to clarify their molecular mechanisms, which would help in the discovery of potential therapeutic targets and in developing a personalized and precise treatment approach for NPC patients. We previously generated a cisplatin-sensitive NPC cell line, S16, from CNE2 cells and found that eIF3a, ASNS and MMP19 are upregulated in S16 cells, which contributes to their cisplatin sensitivity. In this study, we found that BST2 is downregulated in cisplatin-sensitive S16 cells compared with CNE2 cells. Knockdown of BST2 in NPC cells sensitized their response to cisplatin and promoted cisplatin-induced apoptosis, whereas exogenous overexpression of BST2 increased their cisplatin resistance and inhibited cisplatin-induced apoptosis. Further investigation demonstrated that BST2-mediated cisplatin resistance depended on the activation of the NF-κB signaling pathway and consequent upregulation of anti-apoptotic genes, such as Bcl-XL and livin. Moreover, an analysis of clinical data revealed that a high BST2 level might serve as an independent indicator of poor prognosis in patients with locally advanced NPC treated with platinum-based chemoradiotherapy. These findings suggest that BST2 likely mediates platinum resistance in NPC, offering guidance for personalized and precise treatment strategies for patients with NPC.

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Section: Discussionmentioning

confidence: 86%

BST2 confers cisplatin resistance via NF-κB signaling in nasopharyngeal cancer

Kuang

Hua

et al. 2017

Cell Death Dis

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“…A). Interestingly, lung SCC cells (H2066, SW900, H2170, Calu‐1, H520, and SK‐MES‐1), which we previously demonstrated to exhibit decreased sensitivity to cisplatin, were highly sensitive to belinostat (Kong et al ., ). The reciprocally inverse sensitivity among belinostat and cisplatin suggested the potential for synergistic combination.…”

Section: Resultsmentioning

confidence: 97%

“…The present study shows that a belinostat/cisplatin combination is broadly effective across a panel of lung SCC cell lines, with a strong inhibition of MAPK and SOS. Our group has previously described the significance of SOS/MAPK activation in cisplatin resistance (Kong et al ., ). On the basis of this study, we speculate that belinostat treatment promotes ubiquitin‐proteasome activity in SCC cells; however, cisplatin‐resistant cells that exploit SOS/MAPK activation for survival are more susceptible to belinostat treatment.…”

Section: Discussionmentioning

confidence: 97%

“…Son of sevenless is a guanine nucleotide exchange factor that regulates the activation of Ras-GTPases and subsequently induces MAPK signaling (Gureasko et al, 2008;Rogge et al, 1991). It has been shown previously that SOS upregulation leads to cisplatin resistance in lung SCC cells through MAPK/ERK pathway activation (Kong et al, 2015). As belinostat demonstrated strong inhibition of MAPK signaling, we therefore investigated the expression status of SOS upon exposure to belinostat.…”

Section: Belinostat Blocks Sos/mapk Activation In Cisplatin-resistantmentioning

confidence: 99%

“…The current study highlights the therapeutic efficacy of belinostat in lung SCC cells and characterizes the downstream molecular signaling in belinostat-treated cells. We have previously identified activation of MAPK/ERK as a mechanism of resistance to cisplatin (Kong et al, 2015). The increase in ERK phosphorylation upon cisplatin treatment was shown to be regulated by son of sevenless (SOS) upstream.…”

Section: Introductionmentioning

confidence: 99%

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Belinostat exerts antitumor cytotoxicity through the ubiquitin‐proteasome pathway in lung squamous cell carcinoma

et al. 2017

Self Cite

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There have been advances in personalized therapy directed by molecular profiles in lung adenocarcinoma, but not in lung squamous cell carcinoma (SCC). The lack of actionable driver oncogenes in SCC has restricted the use of small‐molecule inhibitors. Here, we show that SCC cell lines displayed differential sensitivities to belinostat, a pan‐histone deacetylase inhibitor. Phosphoproteomic analysis of belinostat‐treated SCC cells revealed significant downregulation of the MAPK pathway, along with the induction of apoptosis. In cisplatin‐resistant cells that demonstrated aberrant MAPK activation, combined treatment with belinostat significantly inhibited cisplatin‐induced ERK phosphorylation and exhibited strong synergistic cytotoxicity. Furthermore, belinostat transcriptionally upregulated the F‐box proteins FBXO3 and FBXW10, which directly targeted son of sevenless (SOS), an upstream regulator of the MAPK pathway, for proteasome‐mediated degradation. Supporting this, suppression of SOS/ERK pathway by belinostat could be abrogated by inhibiting proteasomal activity either with bortezomib or with siRNA knockdown of FBXO3/FBXW10. Taken together, these preclinical data offer a novel understanding of the epigenetic mechanism by which belinostat exerts its cytotoxicity and supports the combination with cisplatin in clinical settings for chemorefractory SCC tumors.

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Nanomedicine Combats Drug Resistance in Lung Cancer

Zheng,

Song,

Zhu

et al. 2023

Advanced Materials

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Lung cancer is the second most prevalent cancer and the leading cause of cancer‐related death worldwide. Surgery, chemotherapy, molecular targeted therapy, immunotherapy and radiotherapy are currently available as treatment methods. However, drug resistance is a significant factor in the failure of lung cancer treatments. Novel therapeutics have been exploited to address complicated resistance mechanisms of lung cancer and the advancement of nanomedicine is extremely promising in terms of overcoming drug resistance. Nanomedicine equipped with multi‐functional and tunable physiochemical properties in alignment with tumor genetic profiles could achieve precise, safe, and effective treatment while minimizing or eradicating drug resistance in cancer. Here, we review the discovered resistance mechanisms for lung cancer chemotherapy, molecular targeted therapy, immunotherapy and radiotherapy, and outline novel strategies for the development of nanomedicine against drug resistance. We focus on engineering design, customized delivery, current challenges and clinical translation of nanomedicine in the application of resistant lung cancer.This article is protected by copyright. All rights reserved

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MEK Inhibition Overcomes Cisplatin Resistance Conferred by SOS/MAPK Pathway Activation in Squamous Cell Carcinoma

Cited by 47 publications

References 48 publications

BST2 confers cisplatin resistance via NF-κB signaling in nasopharyngeal cancer

BST2 confers cisplatin resistance via NF-κB signaling in nasopharyngeal cancer

Belinostat exerts antitumor cytotoxicity through the ubiquitin‐proteasome pathway in lung squamous cell carcinoma

Nanomedicine Combats Drug Resistance in Lung Cancer

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