Abstract 3950: Sensitizing oncogenic mutant p53-expressing non-small cell lung cancer to proteasome inhibitors

Abstract

Abstract Background: Lung cancer is the leading cause of cancer deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for ~80% of all lung cancers. Up to 69% of NSCLC are mutated for the tumor suppressor gene TP53, and of these, 84% are missense mutations, where wild-type (WT) TP53 tumor suppressor function is lost and in most cases, emergent cancer-promoting oncogenic activities are acquired. Due to the poor draggability of mutated p53 protein, the focus of therapeutics targeting NSCLC tumors with oncogenic missense mutant p53 has been on vulnerabilities that are not present in normal cells expressing WT p53. One such vulnerability involves oncogenic mutant p53-dependent attenuation of the oxidative stress response. The ability of cancer cells to survive oxidative stress depends on the regulated synthesis and activity of cellular antioxidants, including glutathione (GSH). Proteasome inhibitors (PIs) are known to induce cellular stress at multiple levels, including proteotoxic, autophagic, and oxidative stress, but the clinical utility of PIs has been limited by lack of efficacy in patients with solid tumors, including unselected lung cancer patients. Methods and Results: We now show bortezomib (BTZ) and other PIs are preferentially cytotoxic in oncogenic mutant p53-expressing lung cancer cells in culture. Furthermore, BTZ-treated oncogenic mutant p53-expressing cells display elevated levels of reactive oxygen species and BTZ’s cytotoxic effects were rescued by antioxidants such as N-acetyl cysteine, indicating that oxidative stress is the critical driver of BTZ cytotoxicity. Upon BTZ treatment of oncogenic mutant p53-expressing NSCLC cells, but not in WT p53 expressing NSCLC cells, we also observed the transcriptional induction of pro-apoptotic BH3-only BCL-2 family protein NOXA, consistent with an apoptotic mechanism of BTZ-induced cell death. Furthermore, in combination with BTZ, the use of BH3-mimetics such as venetoclax (ABT-199) or navitoclax (ABT-263) to inhibit the function of pro-survival proteins BCL-2/BCL-XL synergistically enhanced BTZ cytotoxicity, but only in oncogenic mutant p53-expressing NSCLC cells. In vivo mouse xenograft studies demonstrated that combination treatments of BTZ + venetoclax or BTZ + carboplatin (a standard of care chemotherapy for NSCLC) significantly attenuated oncogenic mutant p53-expressing tumor growth. Conclusions: Our data suggest that the preferential cytotoxicity of BTZ, and potentially other PIs, in oncogenic mutant p53-expressing NSCLC cells depends on the induction of toxic oxidative stress leading to NOXA-dependent apoptosis. Thus, combining PIs with drugs that limit antioxidant responses and/or sensitize cells to NOXA-induced apoptosis (e.g., BH3-mimetics) should synergistically and selectively kill NSCLC cells expressing oncogenic mutant p53 and open novel therapeutic avenues for the treatment of NSCLC. Citation Format: Kranthi Kumar Chougoni, Victoria L. Neely, Boxiao Ding, Eziafa Oduah, Khanh Nguyen, Bin Hu, Jennifer Koblinski, Bradford Windle, Hisashi Harada, Steven Grossman. Sensitizing oncogenic mutant p53-expressing non-small cell lung cancer to proteasome inhibitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3950.