Two sides of the same coin: tyrosine kinase inhibition in cancer and neurodegeneration

Cancer and neurodegeneration include a group of diseases that are mechanistically distinct but may share common therapeutic targets. Autophagy is a common quality control mechanism shared by mitotic and post-mitotic cells and it can be exploited to accelerate clearance of unwanted oncogenes and reduce accumulation of toxic proteins in cancer and neurodegeneration, respectively. Tyrosine kinase inhibition is a therapeutically relevant strategy that can induce autophagy, leading to normal cell survival. This article provides insights into how tyrosine kinase inhibition is clinically used to arrest mitotic cell division and tumor growth, and may promote survival of post-mitotic neurons in neurodegeneration. Neurodegenerative diseases include a group of genetic and sporadic disorders associated with neuronal death and progressive nervous system dysfunction. Cancer is also a collection of related genetic diseases, in which cells begin to divide without stopping and spread into surrounding tissues. Unlike neurodegeneration, in which no regeneration happens when damaged or aging post-mitotic neurons die, damaged cells survive when they should die in cancer, resulting in uncontrolled mitotic cell division to form tumors. Cancerous tumors are malignant as they spread or invade nearby tissues by cellular contiguity or metastasize via blood and/or humoral transport. In neurodegeneration, the spread of disease by contiguity is supported by the hypotheses that toxic or prion-like proteins, like oncogenes, propagate along neuroanatomical pathways (Polymenidou and Cleveland, 2012), leading to progressive spread of disease and cell death. The spread of toxic or misfolded proteins in neurodegeneration may be similar to the spread of metastatic cancer, as both pathologies spread from the place where they originate. In neurodegeneration, failure of cellularquality control mechanisms leads to inadequate protein degradation via the proteasome or autophagy (Ciechanover and Kwon, 2015), resulting in intracellular accumulation of toxic and pathological proteins. Consequently, these proteins are secreted from a pre-synaptic neuron and can traverse the synaptic cleft and enter a contiguous post-synaptic neuron (Figure 1). Secreted proteins may not penetrate an adjacent cell via the synapse but they may be re-routed into the cell and recycled via the endosomal system to fuse with autophagic vacuoles like the autophagosome or the lysosome (Jerram et al., 1996; Mellman, 1996; Luzio et al., 2000). Microglia, the brain resident immune cells may also phagocytose and destroy toxic proteins (Kettenmann et al., 2011). Accumulation of toxic proteins, including alpha-synuclein (Lewy bodies), beta-amyloid plaques, tau tangles, Huntington, prions and TDP-43 are major culprits in neurodegeneration. These toxic proteins trigger progressive apoptotic cell death leading to loss of many CNS functions, including mentation, cognition, movement, gastrointestinal motility, sleep and many others. The discoveries of toxic protein propagation from cell to cell (Polymenidou and Cleveland, 2012), leading to progression