1. Targeting signal transduction
Targeting signal transduction. Growth factor receptor activation by mutation or overexpression, or mutations in oncogenes (such as RAS) or tumor suppressor genes (such as PTEN) can lead to signaling through the phophatidylinositol-3 kinase (PI3K)-AKT, mitogen-activated protein kinase (MAPK)-extracellular signal regulated kinase (ERK), nuclear factor-κB (NF-κB), and transforming growth factor-β (TGFβ) pathways. Such signaling can affect radiosensitivity by decreasing apoptosis (left) or increasing DNA repair (right). AKT, MAPK, and NF-κB signaling can all lead to phosphorylation and inactivation of proapoptotic proteins or activation of antiapoptotic proteins. Altering apoptosis does not always lead to changes in clonogenic cell survival (dashed arrow with question mark). Activation of the AKT and MAPK pathways leads to the activation of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), a central protein in DSB repair by NHEJ. Direct inhibition of DNA repair may also lead to radiosensitization by targeting the ATM and DNA-PKcs kinases or PARP proteins. DNA-PKcs can also be activated by the receptor tyrosine kinase (RTK) epidermal growth factor receptor (EGFR) after it is translocated to the nucleus. There is a strong correlation between DNA repair capacity, particularly for DSBs, and radiosensitivity. Ionizing radiation can also activate the PI3K, MAPK, and NF-κB pathways. Inhibition of signaling pathways following irradiation can therefore reverse (Begg et al, 2011) tumor cell radioresistance. Some inhibitors have also been shown to affect tumor vasculature, leading to improved perfusion and reduced hypoxia (see also Chap. 16, Sec ). Asterisk indicates activation. (Taken from Begg et al, 2011.)
Source: Molecular and Cellular Basis of Radiotherapy, The Basic Science of Oncology, 5e
Citation: Tannock IF, Hill RP, Bristow RG, Harrington L. The Basic Science of Oncology, 5e; 2016 Available at: Accessed: January 01, 2018
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