Chemotherapy versus targeted therapy in high and low NRF2 lung adenocarcinoma.

e20068 Background: Lung cancer remains the leading cause of cancer-related mortality in the United States. Transformation from lung adenocarcinoma (LUAD) to the more aggressive type of lung cancer, neuroendocrine tumors (NE) or squamous cell carcinoma (SCC) is a clinical therapy resistance mechanism observed in non-small cell lung cancer (NSCLC). Alterations in NRF2, an antioxidant gene, is seen in about 30% of NSCLC cases. Our recent studies implicated the NRF2 signaling in the histological transformation in NSCLC. We aimed to determine how NRF2-treatment type interaction contributes to the transformation in NSCLC subtypes and the impact on tumor growth and metastasis. Methods: We used two KRAS-mutant human LUAD cell lines, NRF2 wt/wt -A549 and NRF2 mut/wt -H358. We characterized the cell lines with and without NRF2 activation -/+ carboplatin or sotorasib (KRAS inhibitor) in vitro. We used immunoblotting and IncuCyte technology to determine the differentiation, growth, and invasion before and after treatment -/+ NRF2 activation. Results: Activation of NRF2 in the NRF2 low cell line increases the resistance to both chemo (carboplatin)- and targeted (sotorasib) therapy. Treatment with carboplatin or sotorasib increases the level of NRF2 signaling in NRF2 low and NRF2 high cell lines and induces the differentiation of SCC (with high P63 protein levels), and NE (with high synaptophysin protein levels). These changes increased the invasion of these cells; however, the growth rate was lower post chemotherapy, but increased with higher resistance to targeted therapy (sotorasib). Conclusions: These results show that NRF2 activation impairs the efficacy of sotorasib in LUAD due to transformation to a more aggressive SCC, and to lesser extent NE tumor cells, with high growth rate and invasion. These changes were attenuated post chemotherapy. Further, high growth inhibition was observed with carboplatin treatment in NRF2 low and NRF2 high LUAD cells compared to sotorasib. Therefore, KRAS mutant LUAD should be tested for NRF2 status before making decision on the type of treatment (chemotherapy or targeted therapy) using immunohistochemistry (IHC)-NRF2.