New rationales for using TGFβ inhibitors in radiotherapy

Purpose: The first reports that ionizing radiation ( IR) induces rapid and persistent activation of transforming growth factor beta 1 ( TGF beta) were nearly two decades ago. Subsequent studies have shown that TGF beta 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 TGF beta 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 TGF beta is inhibited. Thus, in conjunction, with its well-recognized contribution to normal tissue fibrosis, the role of TGF beta 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 TGF beta manipulation enhances tumor cell radiosensitivity, while protecting normal tissues, could significantly increase therapeutic index.