ONCAlert | Upfront Therapy for mRCC

Current Role of MET Inhibitors in Cancer Therapy

Xiaoliang Wu, MD, and Patrick C. Ma, MD, MSc
Published Online: Feb 26,2016

Abstract


Over the last several years of clinical MET targeting therapeutics development, mixed clinical trial studies results especially in the phase 3 study outcomes have resulted in disappointment and hurdles in the drug development. More recent advances in technological profiling platforms and their increasingly common implementation to inform therapeutics in cancer therapies have uncovered and validated novel MET alterations especially METex14 juxtamembrane skipping alternative splicing variant, and MET chromosomal fusion products. These findings alongwith some emerging clinical tumor response in MET therapy targeting METex14 in lung adenocarcinoma, soft tissue sarcoma and pulmonary sarcomatoid carcinoma have regenerated new enthusiasm in further exploring MET targeted therapy. It is also becoming clear in recent years that concurrent genomic, proteomics and immune surveillance milieu beyond the identifiable MET alterations could play important roles in determining the ultimate tumor response to MET targeted therapy. These bioinformatics data should be considered essential in modern omics era drug development and in the elucidation of predictive biomarkers. Emerging discoveries of MET chromosomal fusions provide additional promise as therapeutic genomic targets in MET cancer therapy and would need to be tested vigorously.


Introduction


MET is a multifunctional receptor tyrosine kinase (RTK) that normally plays an important role in embryonic developmental signaling. In adulthood tissues and cellular environment, it is primarily activated during tissue injuries and wound healing, otherwise it remains mostly quiescent. Pathologically, MET signaling dysregulation leads to malignant cellular transformation, proliferation, survival, motility and migration, scattering, epithelial-mesenchymal transition (EMT), angiogenesis, invasion, and metastasis.1 The MET protooncogene resides on the 7q31 locus of chromosome 7, consisting of 21 exons separated by 20 introns.2,3 MET is composed of an a-chain (50 kDa) and a transmembrane b-chain (140 kDa) subunit linked by a covalent disulphide bond. The MET b-chain adopts a 7-blade b-propeller fold structural domain within the aminoterminal Semaphorin (or Sema) domain, which has homology with the plexin family of semaphorin receptors.

The Sema domain plays a key role in the ligand binding and receptor homodimerization of MET.4-6 Following the Sema domain is the PSI domain (found in plexins, semaphorins, and integrins), then 4 IPT repeats (found in immunoglobulin, plexins, and transcription factors), and a single a-helix transmembrane domain. The cytoplasmic tyrosine kinase domain contains a number of key serine and tyrosine phosphorylation sites important in the recruitment of SRC-homology-2-domain (SH2) containing signaling transducers and intermediaries. The natural ligand for MET is hepatocyte growth factor (HGF), alternatively called scatter factor (SF), which can be found and is produced in the stromal and mesenchymal cells, acting in endocrine and/or paracrine fashion on the MET- expressing epithelial cells.7 Besides, autocrine tumoral source of HGF can also mediate oncogenic signaling.8-12 Upon ligand binding to HGF, MET is phosphorylated at multiple residues, with subsequent catalytic activation of cellular signaling transduction cascades.13 Phosphorylation of the major autophosphorylation sites Y1230, Y1234, and Y1235, located within the activation loop of the tyrosine kinase domain, activates the intrinsic catalytic MET kinase activity. It leads then to further recruitment of intracellular adaptor molecules through the SH2 domains and other recognition motifs, such as GAB1 (key signaling adaptor coordinator of the cellular responses to MET). Downstream GRB2- mitogen-activated protein kinases (MAPK) signaling cascade, PI3K-mTOR pathway and the STAT signaling pathway are also eventually activated to effectuate various cellular functions.14,15



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Current Role of MET Inhibitors in Cancer Therapy
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