MET Pathway Research Hinges on Finding Right Patient Niche

Jane de Lartigue, PhD
Published: Thursday, May 26, 2016
Enthusiasm for the MET signaling pathway as a target for anticancer therapy has not waned despite several high-profile failures in multiple indications. This persistence appears to be paying off as promising new data emerge from more recent clinical trials, paving the way for active clinical development of nearly 20 new and existing agents (Table).

In addition to its role as an oncogenic driver, the MET pathway has been increasingly implicated in the development of resistance to various types of anticancer therapy. A greater understanding of the molecular mechanisms underlying this role also have prompted the development of combinations that are impacting the treatment landscape for numerous tumor types.

Finding the right patients to be treated with MET inhibitor therapy is the key to their renewed success, but the search is proving anything but straightforward due to the complex nature of responses. As researchers seek to overcome this hurdle, they are redefining the niche for MET-targeted therapies in oncology.

A Promising Target

Since its discovery more than three decades ago, the MET gene has been closely linked to the development of cancer. It was originally identified as one of the genes involved in the transformation of a sarcoma cell line and subsequently found to encode a tyrosine kinase receptor that facilitates the transmission of signals from outside the cell into the nucleus to coordinate cellular responses.

 

Table. MET-Targeting Agents in Clinical Development

MET-Targeting Agents in Clinical Development

ALK indicates anaplastic lymphoma kinase; AML, acute myeloid leukemia; AXL, AXL receptor tyrosine kinase; CRC, colorectal cancer; CRPC, castration- resistant prostate cancer; EGFR, epidermal growth factor receptor; FLT, FMS-related tyrosine kinase; HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; HNSCC, head and neck squamous cell carcinoma; MET, mesenchymal epithelial transition receptor; NSCLC, non–small cell lung cancer; RCC, renal cell carcinoma; RON, recepteur d’origine nantais; ROS, ROS proto-oncogene; TIE, tyrosine kinase with immunoglobulin- like and EGF-like domains; TRK, tropomyosin receptor kinase; VEGFR, vascular endothelial growth factor receptor.

The MET receptor is typically activated by the binding of its only known ligand, hepatocyte growth factor (HGF), although MET signaling can also be initiated independently of the ligand. HGF is secreted from mesenchymal cells as an inactive precursor and is activated by a group of protease enzymes, allowing it to bind to MET, which is located primarily on the surface of epithelial and endothelial cells.

In response to the binding of HGF, a single MET receptor molecule pairs up with another, which triggers its intrinsic kinase activity. Several regions of the receptor subsequently become phosphorylated, including a docking site, which recruits a whole range of intracellular proteins that activate a number of different downstream signaling cascades, including the PI3K/Akt, MAPK, STAT3 and NFκB pathways. These ultimately transmit the MET receptor’s signal to the nucleus, where it triggers the transcription of genes involved in key cellular processes.

In addition to regulating cell growth, survival and proliferation, the MET pathway orchestrates an invasive growth program in normal cells, an important process for embryogenesis and for tissue repair and wound healing in adults.

As part of this program, it coordinates the epithelial to mesenchymal transition (EMT), via which epithelial cells gain mesenchymal cell properties that allow them to break apart from one another and become more motile and invasive.

The roles of MET signaling in normal cells translate into many of the hallmark properties of cancer cells and, since its original discovery as a proto-oncogene, numerous studies have provided evidence that the MET pathway can be hijacked to drive tumorigenesis in a number of different cancer types.


View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: CDK4/6 Inhibitors With the Experts: The Role of Emerging Agents for the Management of Metastatic Breast CancerMay 30, 20182.0
Medical Crossfire®: Clinical Updates on PARP Inhibition and its Evolving Use in the Treatment of CancersMay 30, 20181.5
Publication Bottom Border
Border Publication
x