Receptor tyrosine kinases control cellular functions during development and homeostasis through the activation of signaling pathways leading to cell growth and differentiation. These receptors are shown to be deregulated in cancer and have emerged as promising targets for the development of cancer therapeutics.

A target that has recently attracted much attention is MET, the high-affinity receptor for the hepatocyte growth factor (HGF) mainly expressed on epithelial cells, and a master of epithelial-mesenchymal transition. Deregulated MET is associated with the progression of, and poor prognosis for, a number of cancers including non-small cell lung cancer (NSCLC), gastric, prostate, breast, head and neck, colorectal, and liver. Mechanisms involved in MET deregulation include MET amplification and activating mutations.^1,2

MET is implicated in angiogenesis and shown to act synergistically with VEGFR2. Moreover, MET engages in cross-talks with other membrane proteins including EGFR. MET and EGFR are coexpressed on tumor cells and functionally cooperate to amplify activating signals. Furthermore, MET amplification has been described as a mechanism of resistance to EGFR inhibitors in NSCLC, and more recently preclinical results indicated that MET activation also underlies resistance to HER2 and VEGFR2 inhibitors.^3,4 Thus, the combined inhibition of MET and VEGFR signaling represents a promising approach in cancer treatment by targeting multiple pathways involved in tumor cell survival and angiogenesis.

MethylGene is developing its lead oncology product MGCD265, an oral receptor tyrosine kinase inhibitor that potently inhibits the activation of MET, VEGFR1, 2, 3, Ron, and Tie-2, and impedes the signaling and biological activities mediated by MET and VEGFR2. Importantly, MGCD265 inhibits clinically relevant mutant MET proteins resistant to other MET-selective inhibitors in clinical development. The anti-tumor activity of MGCD265 in MET-driven human xenograft tumor models correlates with the in vivo inhibition of MET phosphorylation and the activation of downstream pathways. MGCD265 also inhibits tumor growth in a broad range of non-MET-driven xenograft models. Furthermore, the combination of MGCD265 with the EGFR inhibitor, erlotinib, leads to improved anti-tumor activities. Improved anti-tumor activity also results from the combination of MGCD265 with chemotherapeutics such as the taxane docetaxel. These results provide a rationale for the clinical development of MGCD265 in combination with docetaxel or erlotinib.

In the ongoing Phase 1 program, MGCD265 is administered orally to patients with advanced cancers. The compound has demonstrated a favorable safety profile and can be combined safely with docetaxel and erlotinib. Over 150 patients have been treated with MGCD265 to date, and in combination with other agents MGCD265 has demonstrated encouraging signs of activity in NSCLC and gastric cancers. MethylGene will further evaluate MGCD265 in these indications in ongoing and future studies.

References
1. Sierra JR and Tsao MS. c-Met as a potential therapeutic target and biomarker in cancer. Ther Adv Med Oncol. 2011;3(S1) S21-S35.

2. Cañadas I, et al. C-MET as a new therapeutic target for the development of novel anticancer drugs. Clin Transl Oncol. 2010;12:253-260.

3. Bean J, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. PNAS. 2004;104(52):20932-7.

4. Bergers G and Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008; 8:592-603.