Abstract 1388: Loss of TGFβ signaling increases alternative end-joining and could sensitize high-grade serous ovarian cancer to PARP inhibitors

Abstract

Abstract Defective DNA damage repair (DDR) is an important therapeutic target in high-grade serous ovarian cancer (HGSOC). This is exemplified by the efficacy of platinum analogues in this disease, as well as the advent of PARP inhibitors that exhibit synthetic lethality when applied to BRCA-mutated tumors. We recently found that loss of transforming growth factor β (TGFβ) signaling in head and neck squamous cell carcinoma causes dysregulation of BRCA1 and hence defective homologous recombination, which pushes cells to rely on error-prone alternative end-joining (alt-EJ) for DDR (Liu et al. Clin Ca Res 2018). To examine this link in ovarian cancer, here we interrogated the transcriptomes from 562 HGSOC patients from The Cancer Genome Atlas Consortium (TCGA) using a 50-gene signature of chronic TGFβ signaling and a 30-gene signature of alt-EJ competency. Our study unveiled a highly significant (p<0.00001) inverse correlation between TGFβ and alt-EJ in HGSOC. Alt-EJ is error prone, thus we examined the fraction of the genome altered as a function of TGFβ/alt-EJ; the TGFβ/alt-EJ pathway index score was negatively associated with the fraction of genome altered (Pearson correlation coefficient: -0.3288887; P-value = 2.9e-15), with tumors with low TGFβ/high alt-EJ exhibiting more genomic alterations. Alt-EJ increases tumor cell sensitivity to radiation and chemotherapy. Patients with low TGFβ/high alt-EJ profile were associated with an overall survival advantage (p=0.02) and a disease-free survival advantage (p=0.03). Consistent with this, patients with low TGFβ/high alt-EJ profile showed a significantly better response to primary treatment with cisplatin (p=0.038). These data support combinations of TGFβ inhibitors that could boost response to chemotherapy in HGSOC. Because PARP enzymes are key to alt-EJ, which sensitizes cells to PARP inhibition (ibid), these data suggest a novel means to identify patients that will likely be responsive to PARP inhibitors independently of BRCA mutational status. Citation Format: Ines Guix, Qi Liu, Luis Palomero, Jade Moore, Miquel Angel Pujana, Mary Helen Barcellos-Hoff. Loss of TGFβ signaling increases alternative end-joining and could sensitize high-grade serous ovarian cancer to PARP inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1388.