Research ArticleCancer

Loss of TGFβ signaling increases alternative end-joining DNA repair that sensitizes to genotoxic therapies across cancer types

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Science Translational Medicine  10 Feb 2021:
Vol. 13, Issue 580, eabc4465
DOI: 10.1126/scitranslmed.abc4465

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Signatures of genotoxic sensitivity

Transforming growth factor–β (TGFβ) has been linked to DNA repair, including error-prone alternative end joining (alt-EJ). Now, Liu et al. show that chemical inhibition of TGFβ signaling promoted a shift to alt-EJ across a variety of cancer cell lines, augmenting sensitivity to ionizing radiation. Gene expression signatures of TGFβ and alt-EJ inversely correlated across a variety of solid cancers, and a low TGFβ/high alt-EJ signature predicted better outcomes after genotoxic therapy in multiple patient cohorts, suggesting the translational potential of these findings.

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