Targeting oncogenic ALK and MET: a promising therapeutic strategy for glioblastoma

Abstract

Glioblastoma is the most common aggressive, highly glycolytic, and lethal brain tumor. In fact, it is among the most commonly diagnosed lethal malignancies, with thousands of new cases reported in the United States each year. Glioblastoma's lethality is derived from a number of factors including highly active pro-mitotic and pro-metastatic pathways. Two factors increasingly associated with the intracellular signaling and transcriptional machinery required for such changes are anaplastic lymphoma kinase (ALK) and the hepatocyte growth factor receptor (HGFR or, more commonly MET). Both receptors are members of the receptor tyrosine kinase (RTK) family, which has itself gained much attention for its role in modulating mitosis, migration, and survival in cancer cells. ALK was first described as a vital oncogene in lymphoma studies, but it has since been connected to many carcinomas, including non-small cell lung cancer and glioblastoma. As the receptor for HGF, MET has also been highly characterized and regulates numerous developmental and wound healing events which, when upregulated in cancer, can promote tumor progression. The wealth of information gathered over the last 30 years regarding these RTKs suggests three downstream cascades that depend upon activation of STAT3, Ras, and AKT. This review outlines the significance of ALK and MET as they relate to glioblastoma, explores the significance of STAT3, Ras, and AKT downstream of ALK/MET, and touches on the potential for new chemotherapeutics targeting ALK and MET to improve glioblastoma patient prognosis.

ALKFusions in a Wide Variety of Tumor Types Respond to Anti-ALK Targeted Therapy

“…The impressive efficacy of targeting f ALK in NSCLC and ALCL raised interest in ALK alterations in other cancer types. Several studies have shown the efficacy of anti‐ALK therapies in a wide variety of malignancies , but these studies are small‐scale and generally limited to individual case reports or case studies. In addition, many of these publications targeted ALK alterations that were not classic gene fusions, and included both ALK gene amplifications and ALK ‐activating base substitutions .…”

15α-methoxypuupehenol Induces Antitumor Effects In Vitro and In Vivo against Human Glioblastoma and Breast Cancer Models

“…Functionally, CyclinB1 is a known regulator of the cell cycle (40), Alk promotes growth and anti-apoptotic pathways (41), while ezrin, radixin, moesin (ERM), and merlin comprise the ERM family of proteins, which link membrane proteins to the actin cytoskeleton (34). Notably, Alk is reportedly overexpressed in GBM tumors (41), ezrin and its functions are associated with tumor cell migration and tumor invasion in GBM and other cancers (42), and with increasing malignancy of astrocytic tumors (43), while merlin causes contact-dependent growth inhibition, decreased proliferation, increased apoptosis, and tumor growth inhibition (44,45). We particularly note the pattern of a seemingly inverse correlation between the expression levels of pS10merlin and the pro-oncogenic pY478ezrin (46) in response to 15α-MP treatment, highlighting the importance of the two genes in the anti-tumor mechanisms of the natural product.…”

Amplification and overexpression of CMET is a common event in brain metastases of non‐small cell lung cancer

“…In summary, we show that CMET overexpression and CMET amplification are commonly found in NSCLC BM and may thus represent a promising therapeutic target. Specific inhibitors of the HGF/CMET axis that may penetrate the blood–brain/blood–tumour barrier are being developed for primary brain tumours such as glioblastoma and may also be rational experimental therapeutics for selected BM patients …”