ERBB and other receptor Tyr kinases in tumor cell radiation responses - mechanisms of resistance, opportunities for radiosensitization

Ionizing radiation in the therapeutic dose range causes the indiscriminate activation of all ERBB and other receptor Tyr kinases (RTKs) expressed by a given tumor cell. This activation results in the simultaneous activation of multiple pathways that converge to major cytoprotective responses with components of stimulation of cell proliferation, enhanced DNA repair and anti-apoptosis. Since all three responses have been linked to increased cellular radioresistance we have demonstrated that the inhibition with tyrphostin Tyr kinase inhibitors or the expression of dominant negative (DN) ERBB1 (EGFR) radiosensitizes human carcinoma and malignant glioma cells both in vitro and in vivo. Despite their simultaneous activation, different ERBB receptors and IGF-1R retain their specificities in preferential signaling to defined pathways, such as ERBB1 to MAPK and ERBB2 and ERBB3 to PI3K and AKT, respectively. These findings have been derived from the combined use of ERBB-specific kinase inhibitors and the over-expression of DN EGFR-CD533 and ERBB2-CD572. This is important since the selective inhibition of ERBB receptors can lead to pronounced compensatory responses that counteract inhibition. Such compensatory responses have been identified for ERBB3 and IGF-1R and occur in concert with SRC. Frequently expressed mutated, constitutively active variants of ERBB1, e.g., EGFRvIII, represent another mechanism that confers radioresistance since these receptors furnish a greatly enhanced MAPK response after irradiation relative to the wild-type receptor. In summary, effective inhibition of ERBB and other RTKs requires knowledge of the ERBB receptor expression profile of tumor cells, needs to disable more than one receptor, and has to consider powerful compensatory responses within the receptor network that counteract the potential therapeutic benefits derived from receptor inhibition