Resistance Mechanism against Trastuzumab in HER2-Positive Cancer Cells and Its Negation by Src Inhibition

Jin, Mei; Nam, Ah Rong; Park, Ji Eun; Bang, Ju Hee; Bang, Yung Jue; Oh, Do Youn

doi:10.1158/1535-7163.mct-16-0669

Cited by 44 publications

(32 citation statements)

References 38 publications

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“…Change of agents at the downstream of targets in PI3K/AKT pathway, such as PTEN and up-regulation of tyrosine kinase receptors are also related to trastuzumab resistance. 7,20,21,22,23 Trastuzumab inhibited cell growth by antagonizing the HER-2 signal transduction pathway. However, previous research demonstrated that elevated concentration of HER-2 in mitochondria exerted stronger trastuzumab resistance in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

NES1/KLK10 promotes trastuzumab resistance via activation of PI3K/AKT signaling pathway in gastric cancer

Tang

Long

Zhao

et al. 2018

J of Cellular Biochemistry

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Trastuzumab, a humanized antibody targeting human epidermal growth factor receptor 2 (HER2), exhibits remarkable therapeutic efficacy against HER2-positive gastric cancer. Acquired resistance to trastuzumab remains a barrier to patient survival and the mechanisms underlying this are still not well understood. The normal epithelial cell-specific-1 (NES1) gene, also named as KLK10, is recognized as a potential therapeutic target for reversing trastuzumab resistance. The aim of this study was to explore the potential role of KLK10 in trastuzumab resistance (TR) gastric cancer cells. We found that KLK10 was significantly upregulated in trastuzumab-resistant cell lines, SGC7901-TR and BGC-823-TR. In addition, down regulation of KLK10 reversed the resistance in trastuzumab resistant cells. Overexpression of KLK10 induced trastuzumab resistance, and activated the PI3K/AKT signaling pathway, while downregulation of KLK10 presented the opposite effects. Moreover, when the PI3K/AKT signaling pathway was inhibited, the effect of KLK10 on resistance was diminished. Furthermore, combination of trastuzumab and PI3K/AKT inhibitor XL147 effectively inhibited tumor growth in KLK10-overexpressing xenografts. Taken together, our findings show that KLK10 promotes trastuzumab resistance, at least in part, through the PI3K/AKT signaling pathway, suggesting that KLK10 is a potentially target to overcome trastuzumab resistance, and the combination might overcome trastuzumab resistance in KLK10-overexpressed gastric cancer patients.

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Section: Discussionmentioning

confidence: 99%

NES1/KLK10 promotes trastuzumab resistance via activation of PI3K/AKT signaling pathway in gastric cancer

Tang

Long

Zhao

et al. 2018

J of Cellular Biochemistry

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“…Nowadays, drug resistance poses a huge threat to treatment for breast cancer. Although Src inhibitors are promising in reversing resistance of HER2 antagonists in patients with HER2‐positive breast cancer, the potency of Src inhibitors is weakened by quickly acquired resistance . In our study, we first identified the mRNA expression profile in cancer cells resistant to Src inhibitor and discovered that increased PAI‐1 might contribute to Src inhibitor resistance.…”

Section: Discussionmentioning

confidence: 97%

“…Although Src inhibitors are promising in reversing resistance of HER2 antagonists in patients with HER2-positive breast cancer, the potency of Src inhibitors is weakened by quickly acquired resistance. 8,18 In our study, we first identified the mRNA expression profile in cancer cells resistant to Src inhibitor and discovered that increased PAI-1 might contribute to Src inhibitor resistance. Moreover, based on our previous findings, we further showed that PAI-1 could promote saracatinib resistance by inducing the secretion of CCL5.…”

Section: Discussionmentioning

confidence: 99%

PAI‐1 induces Src inhibitor resistance via CCL5 in HER2‐positive breast cancer cells

et al. 2018

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Tyrosine kinase Src is overexpressed and activated in various tumors, including breast cancer, and is supposed to promote cancer formation and development. Src inhibitors have been developed recently and have shown efficacy in breast cancer as a single agent or in combination with anti‐HER2 antibodies or chemotherapy. Unfortunately, the potency of Src inhibitor is limited by the development of drug resistance. In our study, we established an Src inhibitor saracatinib‐resistant breast cancer cell line (SKBR‐3/SI) for the first time and by evaluating mRNA expression profile, we found that plasminogen activator inhibitor‐1 (PAI‐1) was upregulated in saracatinib‐resistant cells compared to the parent cells. Further study demonstrated that PAI‐1 might induce saracatinib resistance in breast cancer cells by increasing the secretion of chemokine (C‐C motif) ligand 5 (CCL5). Functional assays showed that PAI‐1 and CCL5 overexpression promoted cell proliferation and migration in breast cancer cells, while inhibition of PAI‐1 and CCL5 decreased cell proliferation and migration in saracatinib‐resistant cells. We also showed that targeting PAI‐1 or CCL5 could reverse saracatinib resistance, which deserves more attention in clinical settings.

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“…The HER2‐FAK interaction allows significant signaling crosstalk between the two, where FAK is required for HER2 oncogenesis and HER2 allows for resistance to FAK‐kinase inhibitors, including phosphorylating kinase‐dead FAK (Benlimame et al, 2005; Marlowe et al, 2016). FAK activation is also involved in the acquired resistance to HER2 inhibitors, trastuzumab, and lapatinib (Huang et al, 2011; Jin et al, 2017; Yang et al, 2010). By being able to disrupt this protein–protein interaction, the effects of both HER2 and FAK on cancerous cells should be drastically limited, possibly allowing for the mitigation of cancer growth/invasion and HER2‐FAK crosstalk signaling.…”

Section: Introductionmentioning

confidence: 99%

Computational‐based discovery of FAK FERM domain chemical probes that inhibit HER2‐FAK cancer signaling

et al. 2020

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The N-terminal FERM domain of focal adhesion kinase (FAK) contributes to FAK scaffolding and interacts with HER2, an oncogene and receptor tyrosine kinase. The interaction between HER2 and FAK drives resistance to FAK-kinase domain inhibitors through FAK Y397 transphosphorylation and FAK re-activation upon inhibition. As such, FAK FERM remains an attractive drug discovery target. In this report, we detail an alternative approach to targeting FAK through virtual screening-based discovery of chemical probes that target FAK FERM. We validated the binding interface between HER2 and FAK using site-directed mutagenesis and GST pulldown experiments. We assessed the ligandability of key-binding residues of HER2 and FAK utilizing computational tools. We developed a virtual screening method to screen ~200,000 compounds against the FAK FERM domain, identifying 20 virtual chemical probes. We performed GST pull-down screening on these compounds, discovering two hits, VS4 and VS14, with nanomolar IC 50 s in disrupting HER2-FAK. We performed further testing, including molecular docking, immunofluorescence, phosphorylation, and cellular invasion assays to evaluate the compounds' biological effects. One probe, VS14, was identified with the ability to block both auto-and transphosphorylation of Y397. In all, these studies identify two new probes that target FAK FERM, enabling future investigation of this domain. K E Y W O R D SFAK FERM domain, focal adhesion kinase, HER2, high-throughput screening, phosphorylation, virtual screening | 585 STAHL eT AL.

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Resistance Mechanism against Trastuzumab in HER2-Positive Cancer Cells and Its Negation by Src Inhibition

Cited by 44 publications

References 38 publications

NES1/KLK10 promotes trastuzumab resistance via activation of PI3K/AKT signaling pathway in gastric cancer

NES1/KLK10 promotes trastuzumab resistance via activation of PI3K/AKT signaling pathway in gastric cancer

PAI‐1 induces Src inhibitor resistance via CCL5 in HER2‐positive breast cancer cells

Computational‐based discovery of FAK FERM domain chemical probes that inhibit HER2‐FAK cancer signaling

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