60P - Understanding and targeting Met signalling in bladder cancer

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Basic Science
Urothelial Cancers
Genitourinary Cancers
Presenter Waleed Badreldin
Citation Annals of Oncology (2017) 28 (suppl_5): v1-v21. 10.1093/annonc/mdx361
Authors W. Badreldin, T. Powles, L. Menard, C. Ho-Yen, S. Kermorgant
  • Tumour Biology, Barts Cancer Institute-Queen Mary University of London, EC1M 6BQ - London/GB

Abstract

Background

Bladder cancer affects 430,000 patients and leads to 165,000 deaths annually worldwide. With no major advances in the management of this disease in the last 2 decades, there is an urgent need to identify therapeutic targets with validated biomarkers. Overexpression of Met, a Receptor Tyrosine Kinase, was shown to correlate with poor prognosis in bladder cancer making it an attractive target. Cabozantinib, a Met inhibitor, showed clinical activity in patients with refractory bladder cancer in a clinical trial. However, little is known about how Met exactly signals in bladder cancer and there are no validated biomarkers. This study aims at unravelling Met signalling in bladder cancer.

Methods

Western blots and confocal/low light microscopy were used to assess Met signalling and its role in wound healing in Transitional Cell Carcinoma (TCC) cells. Met expression was assessed by immunohistochemistry in tissue samples (n = 64).

Results

Met is overexpressed in TCC cells and in 78% of invasive bladder cancer tissues. This was associated with a shorter median survival as compared to Low Met levels (12.97 Vs 18.05 months). Stimulation of TCC cells with Met ligand, Hepatocyte Growth Factor (HGF), triggered Met activation and downstream signalling as well as wound healing, all of which were reduced with Met pharmacological inhibitors including Cabozantinib. The PI3K downstream effector AKT was highly activated upon Met activation. Moreover, class I PI3K inhibition with GDC094 significantly inhibited HGF-dependent wound healing. Interestingly, HGF triggered rapid Met endocytosis in TCC cells. Furthermore, pharmacological inhibition of endocytosis reduced Met downstream signalling.

Conclusions

We report that Met is a major target in invasive bladder cancer. Our results further suggest that PI3K may be considered as a co-target of Met to improve patients’ outcome. It may also be developed as a biomarker to help select patients who may respond to Met targeted therapy. Finally, we report for the first time that, upon HGF stimulation, Met gets rapidly endocytosed in TCC cells. Furthermore, inhibiting endocytosis reduced Met dependent signalling. All together, our results open the way for novel strategies to target invasive bladder cancer.

Clinical trial identification

Legal entity responsible for the study

Queen Mary University of London

Funding

Barts Cancer Institute, Queen Mary University of London

Disclosure

T. Powles: Honoraria: AstraZeneca, Bristol-Myers Squibb, Roche and Merck. Research Funding: AstraZeneca, Roche and Merck.

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L. Menard: Employee: AstraZeneca.

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All other authors have declared no conflicts of interest.

Disclosure

T. Powles: Honoraria: AstraZeneca, Bristol-Myers Squibb, Roche and Merck. Research Funding: AstraZeneca, Roche and Merck.

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L. Menard: Employee: AstraZeneca.

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All other authors have declared no conflicts of interest.

Disclosure

T. Powles: Honoraria: AstraZeneca, Bristol-Myers Squibb, Roche and Merck. Research Funding: AstraZeneca, Roche and Merck.

L. Menard: Employee: AstraZeneca.

All other authors have declared no conflicts of interest.