By carefully mapping the pathway by which PIs kill Onc-p53 NSCLC cells via proteotoxic stress inducing oxidative stress, followed by the induction of an NRF2–ATF3–NOXA signaling cascade and ultimately apoptosis, we have also developed a rational combination of BTZ with navitoclax as a proof of principle for a future clinical trial involving a PI + next-generation BH3-mimetic combination. Here, TP53 is linked to non-small cell lung carcinoma.