Hepatocyte growth factor expression in <i>EGFR</i>-mutant lung cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a Japanese cohort.

Yano, Shuuichi; Yamada, Tomomi; Takeuchi, Susumu; Tachibana, Kazunoshin; Minami, Yuko; Noguchi, Misa; Hirsch, Fred R.

doi:10.1200/jco.2011.29.15_suppl.7531

Cited by 59 publications

(85 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several reports have also shown that high HGF expression is associated with acquired and intrinsic resistance to EGFR-TKI (13,15,16). We here confirmed that activation of MET signaling by HGF overexpression causes EGFR-TKI resistance in PC-9/hHGF cells.…”

Section: Discussionsupporting

confidence: 78%

“…Yano and colleagues observed that about 29% (13 of 45) of patients who did not respond to EGFR-TKI despite having EGFR mutations showed high HGF expression in their tumors (15). Several reports have also shown that high HGF expression is associated with acquired and intrinsic resistance to EGFR-TKI (13,15,16).…”

Section: Discussionmentioning

confidence: 97%

“…Some studies show that other than EGFR T790M, MET amplification and high expression of hepatocyte growth factor (HGF) also cause treatment resistance (10)(11)(12)(13). High HGF expression levels in tumors, even in patients with activating EGFR mutations, are associated with a poor response to EGFR-TKI (14,15) because the HGF-MET pathway, an alternative signaling route to EGFR, is also activated (16).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Combining Onartuzumab with Erlotinib Inhibits Growth of Non–Small Cell Lung Cancer with Activating EGFR Mutations and HGF Overexpression

Sano¹,

Hashimoto²,

Nakatani³

et al. 2015

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Erlotinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI), benefits survival of patients with non-small cell lung cancer (NSCLC) who harbor activating EGFR mutations. However, elevated expression of hepatocyte growth factor (HGF), a ligand of the MET receptor tyrosine kinase, causes erlotinib resistance. Because onartuzumab, a monovalent antibody to MET, blocks HGF-induced MET activation, the addition of onartuzumab to erlotinib may improve therapeutic efficacy. We engineered the human NSCLC cell line PC-9 (MET-positive cells harboring an exon 19 deletion of EGFR) to overexpress hHGF and evaluated the effects of an onartuzumab and erlotinib combination in vitro and in vivo in xenograft models. A stable clone of PC-9/hHGF was less sensitive to erlotinib than the parental PC-9, and the addition of onartuzumab to erlotinib suppressed the proliferation of these cells in vitro. In PC-9/ hHGF xenograft tumors, onartuzumab or erlotinib alone minimally inhibited tumor growth; however, combining onartuzumab and erlotinib markedly suppressed tumor growth. The total MET protein level was decreased in PC-9/hHGF cells, because MET is constitutively phosphorylated by autocrine HGF, leading to its ubiquitination and degradation. Onartuzumab reduced phospho-MET levels, inhibited MET ubiquitination, and consequently restored MET protein levels. Moreover, in NSCLC clinical specimens harboring activating EGFR mutations, more than 30% of patients expressed high levels of HGF. Our findings raised the possibility that patients with NSCLC with EGFR mutations who express high levels of HGF may benefit from onartuzumab and erlotinib combination therapy, and that HGF can be a novel biomarker for selecting such patients.

show abstract

Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Combining Onartuzumab with Erlotinib Inhibits Growth of Non–Small Cell Lung Cancer with Activating EGFR Mutations and HGF Overexpression

Sano¹,

Hashimoto²,

Nakatani³

et al. 2015

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…The same authors subsequently found that high HGF immunohistochemical reactivity was present in 29% of nonresponding patients, and that HGF expression was signifi cantly higher in tumors with acquired resistance than in sensitive ones ( 64 ). Plasma levels of HGF were evaluated by Tanaka and colleagues ( 65 ), who observed that administration of EGFR kinase inhibitors signifi cantly increased plasma HGF levels 15 days after treatment.…”

Section: Non-small Cell Lung Cancermentioning

confidence: 99%

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

Corso

Giordano

2013

Cancer Discovery

View full text Add to dashboard Cite

Targeted therapies have opened new perspectives in clinical oncology. However, clinicians have observed a lack of response in a relevant percentage of patients and frequent relapse in patients who initially respond. Therefore, a compelling challenge is to identify mechanisms underlying resistance and strategies to circumvent these hurdles. A growing body of evidence indicates that MET, the tyrosine kinase receptor for hepatocyte growth factor (HGF), is frequently implicated in resistance to targeted therapies. In this review, we highlight cell-autonomous and non-cell-autonomous mechanisms through which MET drives resistance, and we discuss some unsolved issues related to the selection of patients who could benefi t from combined therapies. Signifi cance:Resistance is, at present, the major limitation to the effi cacy of targeted therapies. Inappropriate MET activation is very frequently implicated in the onset of primary and secondary resistance to these therapies. Deciphering the role of the HGF/MET axis in resistance to different drugs could guide the design of new clinical trials based on combinatorial therapies, and it might help to overcome, or possibly prevent, the onset of resistance. Cancer Discov; 3(9);

show abstract

“…However, despite initial remission, recurrence was observed within 1 or 2 years (median: 12 months) by multiple mechanisms, such as EGFR T790M, MET (an oncogene) amplification, overexpression of hepatocyte growth factor (HGF) and decrease in gene of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). [4][5][6][7][8] Acquired resistance to EGFR-TKIs is usually inevitable. Therefore, explorations of the exact mechanisms and solutions to improve the sensitivity to TKIs are urgently required.…”

Section: Introductionmentioning

confidence: 99%

Phosphatase and tensin homolog deleted on chromosome 10 degradation induced by NEDD4 promotes acquired erlotinib resistance in non–small-cell lung cancer

Sun

Wang

et al. 2017

Tumour Biol.

View full text Add to dashboard Cite

Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors, such as gefitinib and erlotinib, is a critical issue in the treatment of patients with epidermal growth factor receptor mutant-positive non-small-cell lung cancer. Recent evidence suggests that downregulation of gene of phosphatase and tensin homolog deleted on chromosome 10 plays an important role in acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in various types of cancers, including lung cancer. It was reported that the E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated gene (NEDD4) (also known as NEDD4-1) negatively regulated phosphatase and tensin homolog deleted on chromosome 10 protein levels through poly-ubiquitination and proteolysis in carcinomas of the prostate, lung, and bladder. Whether this process plays a role in epidermal growth factor receptor-tyrosine kinase inhibitors resistance in non-small-cell lung cancer has not been studied extensively. In view of this, we investigated the involvement of NEDD4 and phosphatase and tensin homolog deleted on chromosome 10 in acquired erlotinib resistance with tyrosine kinase inhibitor-sensitive (HCC827) or tyrosine kinase inhibitor-resistant (Erlotinib-resistant HCC827/ER cells which harbored exon 19 deletion. Overexpression of NEDD4 in HCC827/ER cells was detected, and the reverse correlation between NEDD4 and phosphatase and tensin homolog deleted on chromosome 10 expression in these cells was also revealed. In HCC827/ER cells with knockdown of NEDD4, phosphatase and tensin homolog deleted on chromosome 10 and p-Akt expressions were decreased; the sensitivity of HCC827/ER cells to erlotinib was partially restored. Similar results were also observed in vivo. In H1650/ER cells harboring both exon 19 and phosphatase and tensin homolog deleted on chromosome 10 deletion, expression of p-Akt and sensitivity to erlotinib were not affected by simple knockdown of NEDD4 but affected after transfection of phosphatase and tensin homolog deleted on chromosome 10 into H1650/ER cells. Our results demonstrate that NEDD4 may promote the acquired resistance of non-small-cell lung cancer cells to erlotinib by decreasing phosphatase and tensin homolog deleted on chromosome 10 protein expression. Targeted decrease in NEDD4 expression may be a potential therapeutic strategy for tyrosine kinase inhibitor-resistant non-small-cell lung cancer. KeywordsPhosphatase and tensin homolog deleted on chromosome 10 degradation, NEDD4, acquired tyrosine kinase inhibitor resistance, non-small-cell lung cancer Date

show abstract

Hepatocyte growth factor expression in EGFR-mutant lung cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a Japanese cohort.

Cited by 59 publications

References 0 publications

Combining Onartuzumab with Erlotinib Inhibits Growth of Non–Small Cell Lung Cancer with Activating EGFR Mutations and HGF Overexpression

Combining Onartuzumab with Erlotinib Inhibits Growth of Non–Small Cell Lung Cancer with Activating EGFR Mutations and HGF Overexpression

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

Phosphatase and tensin homolog deleted on chromosome 10 degradation induced by NEDD4 promotes acquired erlotinib resistance in non–small-cell lung cancer

Contact Info

Product

Resources

About