Oxidative stress as a selective anticancer agent: investigation of a targeted combination strategy for mutant p53 non-small cell lung cancer and other solid tumors.

Despite many efforts, non-small cell lung cancer (NSCLC) has a dismal 5-year survival rate of less than 20% due to frequently occurring therapy resistance. In addition, currently available targeted therapies are only applicable to limited subgroups of patients. The presence of TP53 mutations is associated with resistance to a wide array of therapeutics that are currently used as first-line treatment in NSCLC, including platinum-based therapies and EGFR tyrosine kinase inhibitors. Since TP53 mutations occur in over 50% of all NSCLC patients, there is a pressing medical need for more effective treatment strategies to improve survival of these patients.In this project, we propose an innovative combination strategy which exploits the presence of mutant p53 by targeting the cellular redox balance. Increased oxidative stress is a hallmark of cancer cells, which makes them more vulnerable to induction of reactive oxygen species (ROS). P53 plays a crucial role in sensing and removing oxidative damage to DNA, and inactivating mutations in the TP53 gene attenuate this function. In addition, it was shown that mutant p53 is able to suppress the function of major antioxidant factors. Therefore, mutant p53 renders cancer cells even more susceptible to the induction of oxidative stress. Besides p53, the poly (ADP-ribose) polymerase 1 (PARP-1) protein plays and important role in the repair of ROS-induced DNA-damage. This led us to explore the potential of combining oxidative stress induction, using the compound APR-246, with the targeted inhibition of the PARP-1 protein, using olaparib. In our lab, this combination strategy showed promising in vitro results in NSCLC cell lines, resulting in strong synergistic interactions in the presence of mutant p53.Following our promising data, this project aims to translate this novel and selective combination strategy to the clinic. In this preclinical study we will explore the combination of two oxidative stress-inducing compounds, APR-246 and auranofin, in combination with the PARP-1 inhibitor olaparib. We will study the predictive value of mutant p53 and the role of ROS in the synergistic cytotoxic effects in NSCLC cell lines. Since oxidative stress and mutant p53 are characteristics that are also frequently observed in other tumor types, we will expand our study to pancreatic ductal adenocarcinoma in vitro.

Keywords:ANTITUMOR THERAPY, APOPTOSIS, OXIDATIVE STRESS

Disciplines:Morphological sciences, Oncology