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

Among the pleotropic roles of transforming growth factor-beta (TGF beta) signaling in cancer, its impact on genomic stability is least understood. Inhibition of TGF beta signaling increases use of alternative end joining (alt-EJ), an error-prone DNA repair process that typically functions as a backup pathway if double-strand break repair by homologous recombination or nonhomologous end joining is compromised. However, the consequences of this functional relationship on therapeutic vulnerability in human cancer remain unknown. Here, we show that TGF beta broadly controls the DNA damage response and suppresses alt-EJ genes that are associated with genomic instability. Mechanistically based TGF beta and alt-EJ gene expression signatures were anticorrelated in glioblastoma, squamous cell lung cancer, and serous ovarian cancer. Consistent with error-prone repair, more of the genome was altered in tumors classified as low TGF beta and high alt-EJ, and the corresponding patients had better outcomes. Pan-cancer analysis of solid neoplasms revealed that alt-EJ genes were coordinately expressed and anticorrelated with TGF beta competency in 16 of 17 cancer types tested. Moreover, regardless of cancer type, tumors classified as low TGF beta and high alt-EJ were characterized by an insertion-deletion mutation signature containing short microhomologies and were more sensitive to genotoxic therapy. Collectively, experimental studies revealed that loss or inhibition of TGF beta signaling compromises the DNA damage response, resulting in ineffective repair by alt-EJ. Translation of this mechanistic relationship into gene expression signatures identified a robust anticorrelation that predicts response to genotoxic therapies, thereby expanding the potential therapeutic scope of TGF beta biology.

Automated summary

The study reveals that TGF-beta signaling controls genomic stability by regulating the DNA damage response and inhibiting Alt-EJ gene expression. Tumors classified as low TGF-beta and high Alt-EJ show more genomic alterations and increased sensitivity to genotoxic therapy, suggesting potential therapeutic implications for targeting these pathways in cancer treatment.