Hepatocellular Growth Factor (HGF) and MET receptor tyrosine kinase signalling play important roles in development as well tumorigenesis. In a Nature review article, Comoglio noted:
"Signals generated by the tyrosine kinase receptor Met elicit a complex biological response including cell dissociation, migration, protection from apoptosis, proliferation and differentiation."
They are also involved in liver regeneration and repair (Huh et al., 2004).
HGF and MET have been shown to be active in a wide range of different cancers from bladder cancer to Wilms Tumours, although it is not yet clear in which tumours the pathway is critical to survival or merely over-expressed as a consequence of events.
The pathway is fairly complex, but here is a simple version:
Source: Angion Biomedica
There is a more detailed pathway schematic in Eder et al's paper (see reference below) for those interested.
Activation of HGF or MET, results in downstream signalling of the RAS-ERK and PI3K-mTOR pathways. The EGFR ligand has been excluded from this schematic for simplicity, but you can imagine how they can interact and thus dual inhibition of both will essentially reduce the risk of either cross-talk or feedback between the two, which reactivates the downstream pathways unless inhibited.
Inhibitors in the Pipeline
This year we have discussed several MET inhibitors on this blog, namely:
- Pfizer's crizotinib, which is a weak MET inhibitor, but potent ALK inhibitor
- Combination of MET and EGFR inhibition previously with ARQ-197 (Arqule/Daiichi-Sankyo) in early lung cancer
I did some research on MET inhibitors in the pipeline and was surprised to find that there are over 30 of them in development, with nearly a dozen in the clinic already. ARQ-197 is clearly leading the pack and moving into phase III soon, as I classify PF-2341066 as an ALK inhibitor, since that's where it's most active.
Here are some of the active compounds I recently came across, although not all of them may still be actively pursued:
Most of the others in the clinic are in more generic phase I allcomer solid tumour trials, as companies look for safety and efficacy signals before determining which tumour types to focus on for major development.
Several compounds appear to specifically target both HGF and MET, eg MetMAB (Roche) and AMG102 (Amgen), whereas others target purely c-MET eg ARQ-197 and some are multi-kinase Inhibitors, eg XL880 and MK-2461, so it remains to be seen which approach will ultimately work best with these agents, and in what combinations for different tumour types.
Single agent vs combination?
Undoubtedly, the data so far suggests that dual inhibition with an EGFR inhibitor such as erlotinib will be more effective than single agent targeting of MET alone.
A recent paper in Cancer Research on MET, HGF and EGFR inhibition with SGX523 (SGX Pharma and Lilly) therefore piqued my interest. I actually thought this compound had been discontinued, following unexpected toxicities two years ago (see here and here), principally compromised kidney function, but it may have been revived by the research group, as the two latest published papers are from late 2009 and last month and Lilly acquired the biotech company in 2008.
The authors looked at a SCID mouse model with the goal of predicting efficacy. Indeed, they concluded that:
"Our findings also indicate that simultaneously targeting the MET and EGFR pathways can provide synergistic inhibitory effects for the treatment of cancers in which both pathways are activated."
Looking at the data though, most of the tumour suppression occurred when SGX523 was combined with erlotinib than either alone as a single agent, suggesting this approach may have more utility in the clinic.
Zhang YW, Staal B, Essenburg C, Su Y, Kang L, West R, Kaufman D, Dekoning T, Eagleson B, Buchanan SG, & Vande Woude GF (2010). MET Kinase Inhibitor SGX523 Synergizes with Epidermal Growth Factor Receptor Inhibitor Erlotinib in a Hepatocyte Growth Factor-Dependent Fashion to Suppress Carcinoma Growth. Cancer research, 70 (17), 6880-90 PMID: 20643778
Buchanan SG, Hendle J, Lee PS, Smith CR, Bounaud PY, Jessen KA, Tang CM, Huser NH, Felce JD, Froning KJ, Peterman MC, Aubol BE, Gessert SF, Sauder JM, Schwinn KD, Russell M, Rooney IA, Adams J, Leon BC, Do TH, Blaney JM, Sprengeler PA, Thompson DA, Smyth L, Pelletier LA, Atwell S, Holme K, Wasserman SR, Emtage S, Burley SK, & Reich SH (2009). SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo. Molecular cancer therapeutics, 8 (12), 3181-90 PMID: 19934279
Comoglio PM (2001). Pathway specificity for Met signalling. Nature cell biology, 3 (7) PMID: 11433311
Huh CG, Factor VM, Sánchez A, Uchida K, Conner EA, & Thorgeirsson SS (2004). Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proceedings of the National Academy of Sciences of the United States of America, 101 (13), 4477-82 PMID: 15070743
Comoglio PM, Giordano S, & Trusolino L (2008). Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nature reviews. Drug discovery, 7 (6), 504-16 PMID: 18511928
Eder JP, Vande Woude GF, Boerner SA, & LoRusso PM (2009). Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 15 (7), 2207-14 PMID: 19318488