A nanomechanical strategy involving focal adhesion kinase for overcoming drug resistance in breast cancer

Choi, Jinsol; Park, Soyeun

doi:10.1016/j.nano.2022.102559

Cited by 4 publications

(3 citation statements)

References 49 publications

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“…48,49 Our previous data demonstrated that FAK plays a crucial role in hepatocarcinogenesis in mouse models. [16][17][18] Furthermore, FAK has been reported to be a key player in chemo-and targeted drug-resistance in various solid tumors, such as lung, 19,20 head and neck, 21 and breast 22 cancers, where FAK inhibition provoked effective growth inhibition and apoptosis in acquired resistant cells and xenografts. For example, acquired resistant HCC exhibited upregulated and persistent FAK phosphorylation, which mediated doxorubicin (DOX) resistance in HCC patient samples and cell lines; however, FAK signaling suppression sensitized DOX-resistant HCC cells to DOX treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Focal adhesion kinase (FAK), as a cytoplasmic nonreceptor tyrosin protein kinase (PTK2), has been demonstrated playing a crucial role in HCC development in our previous findings together with others. [15][16][17][18] Furthermore, FAK has been reported to be a key player in chemo-and targeted drugresistance in various solid tumors, such as lung, 19,20 head and neck, 21 and breast 22 cancers. However, the role of FAK in drug resistance in liver cancer remains largely unclear.…”

Section: Introductionmentioning

confidence: 99%

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Focal adhesion kinase confers lenvatinib resistance in hepatocellular carcinoma via the regulation of lysine‐deficient kinase 1

Hou,

Gad,

Ding

et al. 2023

Molecular Carcinogenesis

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Lenvatinib is a clinically effective multikinase inhibitor approved for first‐line therapy of advanced hepatocellular carcinoma (HCC). Although resistance against lenvatinib often emerges and limits its antitumor activity, the underlying molecular mechanisms involved in endogenous and acquired resistance remain elusive. In this study, we identified focal adhesion kinase (FAK) as a critical contributor to lenvatinib resistance in HCC. The elevated expression and phosphorylation of FAK were observed in both acquired and endogenous lenvatinib‐resistant (LR) HCC cells. Furthermore, inhibition of FAK reversed lenvatinib resistance in vitro and in vivo. Mechanistically, FAK promoted lenvatinib resistance through regulating lysine‐deficient kinase 1 (WNK1). Phosphorylation of WNK1 was significantly increased in LR‐HCC cells. Further, WNK1 inhibitor WNK463 resensitized either established or endogenous LR‐HCC cells to lenvatinib treatment. In addition, overexpression of WNK1 desensitized parental HCC cells to lenvatinib treatment. Conclusively, our results establish a crucial role and novel mechanism of FAK in lenvatinib resistance and suggest that targeting the FAK/WNK1 axis is a promising therapeutic strategy in HCC patients showing lenvatinib resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Focal adhesion kinase confers lenvatinib resistance in hepatocellular carcinoma via the regulation of lysine‐deficient kinase 1

Hou,

Gad,

Ding

et al. 2023

Molecular Carcinogenesis

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“…Focal adhesion kinase (FAK) is reported to be crucial in modulating integrin-dependent cell motility, which induces mechanical force transduction, thus raise nuclear YAP/TAZ [26,27]. Both YAP/TAZ and FAK signaling were proven to play irreplaceable roles in maintaining cancer cell stemness and accelerate chemotherapy resisitance [28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

TMEM120B strengthens breast cancer cell stemness and accelerates chemotherapy resistance via β1-integrin/FAK-TAZ-mTOR signaling axis by binding to MYH9

Hu,

Cao,

Wang

et al. 2024

Breast Cancer Res

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Background Breast cancer stem cell (CSC) expansion results in tumor progression and chemoresistance; however, the modulation of CSC pluripotency remains unexplored. Transmembrane protein 120B (TMEM120B) is a newly discovered protein expressed in human tissues, especially in malignant tissues; however, its role in CSC expansion has not been studied. This study aimed to determine the role of TMEM120B in transcriptional coactivator with PDZ-binding motif (TAZ)-mediated CSC expansion and chemotherapy resistance. Methods Both bioinformatics analysis and immunohistochemistry assays were performed to examine expression patterns of TMEM120B in lung, breast, gastric, colon, and ovarian cancers. Clinicopathological factors and overall survival were also evaluated. Next, colony formation assay, MTT assay, EdU assay, transwell assay, wound healing assay, flow cytometric analysis, sphere formation assay, western blotting analysis, mouse xenograft model analysis, RNA-sequencing assay, immunofluorescence assay, and reverse transcriptase-polymerase chain reaction were performed to investigate the effect of TMEM120B interaction on proliferation, invasion, stemness, chemotherapy sensitivity, and integrin/FAK/TAZ/mTOR activation. Further, liquid chromatography–tandem mass spectrometry analysis, GST pull-down assay, and immunoprecipitation assays were performed to evaluate the interactions between TMEM120B, myosin heavy chain 9 (MYH9), and CUL9. Results TMEM120B expression was elevated in lung, breast, gastric, colon, and ovarian cancers. TMEM120B expression positively correlated with advanced TNM stage, lymph node metastasis, and poor prognosis. Overexpression of TMEM120B promoted breast cancer cell proliferation, invasion, and stemness by activating TAZ-mTOR signaling. TMEM120B directly bound to the coil-coil domain of MYH9, which accelerated the assembly of focal adhesions (FAs) and facilitated the translocation of TAZ. Furthermore, TMEM120B stabilized MYH9 by preventing its degradation by CUL9 in a ubiquitin-dependent manner. Overexpression of TMEM120B enhanced resistance to docetaxel and doxorubicin. Conversely, overexpression of TMEM120B-∆CCD delayed the formation of FAs, suppressed TAZ-mTOR signaling, and abrogated chemotherapy resistance. TMEM120B expression was elevated in breast cancer patients with poor treatment outcomes (Miller/Payne grades 1–2) than in those with better outcomes (Miller/Payne grades 3–5). Conclusions Our study reveals that TMEM120B bound to and stabilized MYH9 by preventing its degradation. This interaction activated the β1-integrin/FAK-TAZ-mTOR signaling axis, maintaining stemness and accelerating chemotherapy resistance.

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Drug resistance mechanisms in dopamine agonist-resistant prolactin pituitary neuroendocrine tumors and exploration for new drugs

Cheng,

Xie,

Chen

et al. 2024

Drug Resistance Updates

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A nanomechanical strategy involving focal adhesion kinase for overcoming drug resistance in breast cancer

Cited by 4 publications

References 49 publications

Focal adhesion kinase confers lenvatinib resistance in hepatocellular carcinoma via the regulation of lysine‐deficient kinase 1

Focal adhesion kinase confers lenvatinib resistance in hepatocellular carcinoma via the regulation of lysine‐deficient kinase 1

TMEM120B strengthens breast cancer cell stemness and accelerates chemotherapy resistance via β1-integrin/FAK-TAZ-mTOR signaling axis by binding to MYH9

Drug resistance mechanisms in dopamine agonist-resistant prolactin pituitary neuroendocrine tumors and exploration for new drugs

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