In cancer, tyrosine kinase mutations are quite common. MET tyrosine kinase is one such example that normally binds its native ligand, hepatocyte growth factor (HGF), and activates several pathways including Src, STAT3, and PI3K-Akt-mTor. MET has been associated with many human carcinomas including breast cancer, and usually is a sign of a poor survival rate. A group based in Singapore decided to investigate MET’s possible role in these cancers, specifically the mutant METN375S.
They began by gathering a cohort of samples with head and neck squamous cell carcinomas (HNSCC), and lung squamous cell cancer (LUSC) all at various stages. After normalizing the treatment amongst the cohorts, they found that the presence of METN375S was a sign of a short recurrence free survival (RFS). Introducing the METN375S mutation in LUSC cells increased oncogenic properties, and xenografts of LUSC cells showed an increased growth rate of the mutant MET compared to normal MET. Trying to abrogate this phenotype in METN375S containing tumors by the application of MET inhibitors did not work however, inferring MET is not the sole player causing the phenotype.
Further investigation led the group to conduct in vivo binding screens, and the tyrosine kinase HER2 was found to be a strong binding partner to the METN375S. HER2 is already associated with aggressive breast cancer progression, and normally is a signal transducer in cellular proliferation. Continuing with this find, a screen of MET, METN375S, and other known MET mutations was conducted and only the METN375S mutant bound tightly as compared to wild type MET.
Taking this interaction into account, the group began testing whether HER2 inhibitors might succeed where MET inhibitors failed in extending the survival rate in METN375S-positive tumors. Application of HER2 inhibitors effectively prevented the interaction between the two kinases, although it did not prevent the hyperactivation of HER2 in some cases. HER2 inhibitors were found to neutralize cell invasion in METN375S-positive tumors as compared to controls. This was particularly true with inhibitors lapatinib and trastuzumab. In vivo experiments in mice found that another HER2 inhibitor, afitinib, even increased overall survival rates.
Although not a direct oncogenic driver of cancer, the group states “Patients with HNSCC and LUSC who carry the METN375S polymorphism have higher risk of disease recurrence”. They are following this study up with clinical trials, investigating the usefulness of the HER2 inhibitors that were effective in this study on METN375S-positive HNSCC and LUSC.
Sources: Nature, ASCOcancer