Data from Oncogenic Mutant <i>p53</i> Sensitizes Non–Small Cell Lung Cancer Cells to Proteasome Inhibition via Oxidative Stress–Dependent Induction of Mitochondrial Apoptosis

<div>Abstract<p>Non–small cell lung cancer (NSCLC) cells with oncogenic mutant <i>p53</i> (<i>Onc-p53</i>) alleles exhibit significantly higher levels of proteasome activity, indicating that Onc-p53 induces proteotoxic stress which may be leveraged as a therapeutic vulnerability. Proteasome inhibitors (PI) are most active in cells under proteotoxic stress, so we investigated whether PIs exhibit preferential cytotoxicity in <i>Onc-p53</i> NSCLC cells. Indeed, bortezomib (BTZ) and other PIs exhibited IC₅₀ values 6- to 15-fold lower in <i>Onc-p53</i> cells versus <i>wild-</i><i>type</i><i> (WT) </i><i>p53</i> cells. BTZ cytotoxic effects in <i>Onc-</i><i>p53</i> cells were abrogated by antioxidants such as <i>N</i>-acetyl-L-cysteine, indicating that oxidative stress is the critical driver of BTZ-dependent cytotoxic effects in <i>Onc-p53</i> cells. Importantly, we observed oxidative stress–dependent transcriptional induction of the proapoptotic BH3-only protein NOXA, leading to cleavage of caspase-3, consistent with an apoptotic mechanism of cell death in <i>Onc-p53</i> but not in <i>WT p53</i> cells treated with BTZ. BTZ-generated oxidative stress was linked to nuclear translocation of NRF2 and transcriptional activation of ATF3, which in turn was required for NOXA induction. Validating the translational potential of BTZ in <i>Onc-p53</i> NSCLC cells, BTZ and the BH3-mimetic navitoclax were synergistically cytotoxic in <i>Onc-p53</i> but not in <i>WT</i><i>p53</i> cells <i>in vitro</i>, and BTZ effectively limited the growth of <i>Onc-p53</i> NSCLC xenografts when combined with navitoclax and carboplatin (a standard-of-care chemotherapeutic in NSCLC) <i>in vivo</i>. Our data therefore support further investigation of the therapeutic utility of PIs combined with BH3-mimetics and chemotherapy in <i>Onc-p53</i> human NSCLC as a novel therapeutic strategy.</p>Significance:<p>NSCLC is the leading cause of cancer death due, in part, to a lack of active therapies in advanced disease. We demonstrate that combination therapy with a proteasome inhibitor, BH3-mimetic, and chemotherapy is an active precision therapy in NSCLC cells and tumors expressing <i>Onc-p53</i> alleles.</p></div>

Duke Scholars

Author Eziafa I Oduah Medicine, Medical Oncology