Dual inhibition of DNA-PK and DNA polymerase theta overcomes radiation resistance induced by p53 deficiency

Rashmi Kumar (1) , Hui Xiao Chao (2) , Dennis Simpson (1) , Wanjuan Feng (1) , Min-Guk Cho (1) , Victoria Roberts (1) , Aurora Sullivan (1) , Sonam Shah (1) , Anne-Sophie Wozny (1, 3) , Katerina Fagan-Solis (1) , Sunil Kumar (1) , Adam Luthman (1) , Dale Ramsden (1) , Jeremy e Purvis (2) , Gaorav Gupta (2, 1)

1 UNC Lineberger - Lineberger Comprehensive Cancer Center
2 Curriculum in Bioinformatics and Computational Biology
3 IP2I Lyon - Institut de Physique des 2 Infinis de Lyon

TP53 deficiency in cancer is associated with poor patient outcomes and resistance to DNA damaging therapies. However, the mechanisms underlying treatment resistance in p53-deficient cells remain poorly characterized. Using live cell imaging of DNA double-strand breaks (DSBs) and cell cycle state transitions, we show that p53-deficient cells exhibit accelerated repair of radiomimetic-induced DSBs arising in S phase. Low-dose DNA-dependent protein kinase (DNA-PK) inhibition increases the S-phase DSB burden in p53-deficient cells, resulting in elevated rates of mitotic catastrophe. However, a subset of p53-deficient cells exhibits intrinsic resistance to radiomimetic-induced DSBs despite DNA-PK inhibition. We show that p53-deficient cells under DNA-PK inhibition utilize DNA polymerase theta (Pol θ)-mediated end joining repair to promote their viability in response to therapy-induced DSBs. Pol θ inhibition selectively increases S-phase DSB burden after radiomimetic therapy and promotes prolonged G2 arrest. Dual inhibition of DNA-PK and Pol θ restores radiation sensitivity in p53-deficient cells as well as in p53-mutant breast cancer cell lines. Thus, combination targeting of DNA-PK- and Pol θ-dependent end joining repair represents a promising strategy for overcoming resistance to DNA damaging therapies in p53-deficient cancers.

Domaines: Cancer

Rashmi Kumar, Hui Xiao Chao, Dennis Simpson, Wanjuan Feng, Min-Guk Cho, et al.. Dual inhibition of DNA-PK and DNA polymerase theta overcomes radiation resistance induced by p53 deficiency. NAR Cancer, 2020, 2 (4), ⟨10.1093/narcan/zcaa038⟩. ⟨hal-03133102⟩