MET/HGF pathway in multiple myeloma: from diagnosis to targeted therapy?

Abstract

The interaction between neoplastic cells and the microenvironment is critical in several cancers and plays a central role in multiple myeloma. Microenvironmental stimuli support plasma cell proliferation, survival, motility and can determine drug resistance. The network between plasma cells and surrounding cells is also responsible for increasing angiogenesis, unbalancing bone formation and bony lesions. The MET/HGF pathway is a key player in this interaction and has been found to be abnormally active in both malignant plasma cells and surrounding cells. Patients with abnormal MET and/or HGF levels usually have a poor outcome even when treated with novel drugs. This review addresses the role of MET/HGF in the pathogenesis of myeloma and describes the role of MET/HGF signaling as a prognostic factor. The different techniques to detect MET/HGF abnormalities are examined and a description of compounds targeting MET/HGF is also provided.

Keywords:

• HGF
• MET
• myeloma
• prognosis
• target therapy

Acknowledgements

The authors would like to thank L Trusolino for the critical review of the manuscript and G Schirripa for editorial assistance.

Financial & competing interests disclosure

A Palumbo has received consultancy fees from Amgen, Bristol-Myers Squibb, Genmab A/S, Celgene, Janssen-Cilag, Millennium Pharmaceuticals Inc. and Onyx Pharmaceuticals. A Palumbo has received honoraria from Amgen, Novartis, Bristol-Myers Squibb, Genmab A/S, Celgene, Janssen-Cilag, Millennium Pharmaceuticals Inc, Onyx Pharmaceuticals and Sanofi Aventis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• MET/HGF pathway is abnormal in MM plasma cells and plays a role in the pathogenesis of MM.

• Abnormalities in MET/HGF increase angiogenesis and cause bone disease.

• MET/HGF abnormalities usually characterize patients with poor prognosis.

• Targeting MET/HGF results in cell death and can attenuate resistance to chemotherapy.

• A reliable marker of sensitivity to anti-MET/HGF treatment is needed to identify patients who would benefit the most from anti MET therapy.

• Biomarker analysis should require easy standard procedures to become a part of the routine diagnostic procedure for MM patients.

• Compounds targeting the MET/HGF pathway will likely be used in combination with chemotherapy agents.

• Early identification of resistance to treatment will be critical in patients treated with MET inhibitors.