APR-246 is a first-in-class small molecule drug that reactivates mutant-p53, re-establishing its tumour suppressor capacity (1). Pre-clinical data show that APR-246 also functions independently of p53 to promote cell death through inhibition of the antioxidants glutathione and thioredoxin, even in p53-null cancer cells (2). Data from the NCI-60 human tumour cell line drug screen show a strong negative correlation between APR-246 activity and expression of genes central to antioxidant homeostasis, such as transketolase (TKT). Whilst studies have explored the mechanisms of mutant-p53, APR-246 and TKT individually, this work uniquely addresses these three aspects in combination by investigating their interrelated roles in redox balance. In this study, the previously resistant p53-null H1299 cells were sensitised to APR-246 through genetic knockdown of TKT whilst the mutant-p53-overexpressing variants H1299-p53R273H and H1299-p53R175H exhibited no change in sensitivity. Additionally, overexpression of TKT enhanced resistance to the drug in only the p53-null cell line. Interestingly, despite selectively altering sensitivity to APR-246 in p53-null cells, changes to oxidative stress levels in response to TKT modulation were comparable across all cell variants. This suggests an alternative role of TKT as the cause of this altered sensitivity, independent of its role in maintaining redox balance. This work identified TKT as a potential biomarker for APR-246 sensitivity in p53-null cells as well as novel potential roles for mutant-p53 and reactivated mutant-p53 in chemoresistance. Taken more broadly, continued work in this area may lend to improved comprehension of the development of drug resistance in mut-p53 tumours and the identification of effective combinatorial therapies for p53-null cancers.