Oncogenic Expression
c-Met is overexpressed and has prognostic significance in a variety of solid tumors:
- breast cancer (20-30%)4
- non-small cell lung cancer (37-67%; IHC ≥2+)5
- gastric cancer (50%)6
- colorectal cancer (61%)7
- head and neck cancer (up to 80%)8
- kidney cancer (~32%)9
- pancreatic cancer (40-60%)10
Due to the redundant activation of c-Met-directed pathways, c-Met expression on tumors by itself is not a sufficient predictor for activity of small molecule inhibitors.11,12
- The antitumor activity of c-Met inhibitors is generally limited to a subset of patients with tumors that are driven predominately by MET signaling.
- Necessitates selection of patients with MET amplification.
Antibody drug conjugates (ADCs) targeting c-Met represent an attractive therapeutic strategy that does not depend on inhibition of downstream signaling for efficacy but rather on target expression.11,13
- c-Met protein expression is significantly higher in many cancers compared with normal tissues.
High c-Met expression has been found in NSCLC tumor samples harboring an EGFR mutation.12
- 50% of primary EGFR-TKI-naive NSCLC tumors showed high c-Met expression while only 3% showed c-Met amplification.12
- A significant correlation was found between c-Met expression and EGFR mutations (p = 0.029).12
In advanced-stage NSCLC, MET mutations have a deleterious effect on overall survival (hazard ratio 23.65; p = 0.005) and indicate poor prognosis.14