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.

Figure 1. Downstream effectors: STAT3, RAS, AKT

ALK/MET mediated phosphorylating activation of STAT3, Ras, and AKT result in expression of numerous distinct, yet interconnected pro-survival, pro-mitotic, and pro-metastatic pathways. While STAT3 acts directly as a transcription factor, Ras and AKT cascades begin at the membrane and are connected by the PI3K/PIPx/PTEN modality.

Figure 2. STAT3 transcriptional activation

Phospho-STAT3 dimerizes with other STAT proteins upon translocation to the nucleus where it potentiates transcription of: c-myc, Pim-1, p21, and IGFBP-5. Among other transcripts, production of Cdc25A by c-myc and Pim-1 directly contributes to the G1 to S phase transition. p-STAT3 inhibits IGFBP-5 to promote an IGF-1 autocrine loop. The IGF-1 autocrine loop thus contributes to production of cell growth signaling and contributes to increased: VEGF, HIF-1α, TLR9, IGF. *p21 activities are numerous, but here it suppresses mitosis and survival protein production; **IGF initiates numerous other pro-mitotic/survival/metastatic cascades

Figure 3. Ras: dual oncogenic pathways

Ras activation further potentiates AKT activation by stimulating PI3K mediated phosphorylation of PIP2 to PIP3; this process is inhibited in the presence of functional PTEN. Ras/Rac activities work with AKT to further stabilize β-catenin activity and thus promote the pro-metastatic adherin product, E-cadherin. Ras/Raf activity triggers activation of the Raf/MEK/ERK cascade which culminates in, among others, increased transcriptional activity of the ETS-ELK-1 complex to further activate pro-mitotic and pro-survival pathways. Ras mediated ELK-1 activation results in an autocrine HGF/MET feedback loop which may further stabilize cell survival and metastatic potential. *Represents another point of interaction with AKT

Figure 4. AKT in oncogenesis

ALK/MET activation results in activation of Ras and AKT. AKT activation inhibits various tonic inhibitors of mitotic and survival cascades including: p53 (downstream of AKT-MDM2 activation), FOXO (promotes transcription of pro-apoptotic genes like BIM and FASL), Caspase-9, Bad, TSC2 (inactivates pro-translational properties of mTOR), and Gsk3β (an integral component of the complex responsible for β-catenin degradation). AKT also activates pro-survival gene transcription through NFκB and, via mTOR disinhibition, potentiates expression of pro-mitotic factors like Survivin, which is highly expressed in glioblastoma. *NFκB & mTOR direct numerous other pro-survival activities not shown here; **Represents another point of interaction with Ras.