MET and ALK in glioblastoma multiforme (GBM): Comparison of IHC and FISH.

Abstract

2021 Background: GBM, the most common and lethal malignant primary brain tumor in adults, has an overall one-year life expectancy of 33.7%. Personalized medicine on the basis of predictive biomarkers remains elusive in GBM; however a recent case report showed clinical improvement after treatment with a mesenchymal-epithelial transition (MET) inhibitor. The authors of that report ascribe clinical response to the MET inhibitor, but the drug is also an inhibitor of anaplastic lymphoma kinase (ALK). We explored the co-expression, gain, or amplification of both MET and ALK by IHC and FISH in GBM. Methods: A convenience sample of 56 available tumors from gross-resected GBM cases within the Duke Brain Tumor tissue bank was stained for MET using clone 8F11 (Leica) and for ALK using clone 5A4 (Novocastra). FISH employed the LSI ALK (2p23) breakpoint-spanning dual-color DNA probe and the LSI D7S486 (MET)/CEP 7 dual color DNA probe (Vysis). Results: Of 56 GBM cases, MET was expressed in 69.6% and ALK in 17.9% by IHC. By FISH, gain or amplification was found in 100% of cases for MET and in 48.2% for ALK. Co-expression of MET and ALK by IHC was 14.3% and 48.2% by FISH. Co-expression by either IHC or FISH was also 48.2%. OS estimation for this cohort is premature, with 77% of patients still alive. Conclusions: MET and ALK are (co-)expressed in a significant proportion of GBM. IHC detection of MET and ALK did not correlate well with FISH results, suggesting that gene gain or amplification does not necessarily lead to abnormal MET and ALK protein expression or that IHC methods or antibodies used can be optimized. Prior studies reported MET amplification in GBM as low as 4%. Our study indicates that MET gain/amplification and protein expression may be much higher, having implications for MET-targeted therapy. Additionally, co-expression of ALK and MET has implications for dual inhibitors of these signaling pathways as well as resistance mechanisms. Our continued work will explore significance of MET and ALK as predictors of therapeutic response, with careful control for clinically relevant patient and disease characteristics. [Table: see text]