New rationales for using TGFβ inhibitors in radiotherapy

Abstract

Purpose: The first reports that ionizing radiation (IR) induces rapid and persistent activation of transforming growth factor β1 (TGFβ) were nearly two decades ago. Subsequent studies have shown that TGFβ is a major mediator of cellular and tissue responses to IR and have revealed novel facets of its complex biology. Results: We and others have recently shown that inhibition of production or signaling of TGFβ in epithelial cells modulates radiosensitivity and impedes activation of the DNA damage response program. The primary transducer of cellular response to DNA damage caused by ionizing radiation is the nuclear protein kinase ataxia telangiectasia mutated, whose activity is severely compromised when TGFβ is inhibited. Thus, in conjunction, with its well-recognized contribution to normal tissue fibrosis, the role of TGFβ in the genotoxic stress program provides a previously unsuspected avenue to modulate radiotherapy. Conclusions: We hypothesize that identification of the circumstances and tumors in which TGFβ manipulation enhances tumor cell radiosensitivity, while protecting normal tissues, could significantly increase therapeutic index. © 2007 Informa UK Ltd.