Impact of KEAP1/NRF2 on therapy response in lung neuroendocrine cancers

SUMMARY SCLC is exquisitely sensitive to chemotherapy but rapid emergence of chemoresistance leads to extremely poor outcomes. We performed genetic screens in patient derived xenograft (PDX) models of SCLC that revealed KEAP1 as a gene for which deletion confers chemoresistance. KEAP1 is the negative regulator for NRF2 (NFE2L2), a transcription factor and master regulator of anti-oxidant responses. While this pathway has not been thought important for SCLC, interrogating genomic data from the IMpower133 clinical trial and mining mutation databases, we find that KEAP1 and NFE2L2 are indeed targets of pathogenic gene alterations in SCLC and that a subset of patients have activation of an NRF2 gene signature. Moreover, this signature strongly associated with worse survival in the chemotherapy arm of IMpower133. Like SCLC, large cell neuroendocrine carcinomas (LCNEC) are aggressive cancers with high recurrence rates and poor outcomes. More than 20% of LCNECs harbor NRF2 pathway activating mutations. We hypothesize that de novo and treatment-evolved mutations in KEAP1 or NFE2L2 drives chemoresistance in SCLC and LCNEC. We further hypothesize that small molecule inhibition of NRF2 will sensitize to cisplatin-etoposide (CIS-ETO) and immune checkpoint inhibitors, which is first-line therapy for SCLC. In Aim 1, we will leverage a panel of genetically perturbed PDX models of SCLC and LCNEC to determine if NRF2 activation or deletion governs CIS-ETO response in vivo. Cancer-derived mutations in KEAP1 and NRF2 will be tested. Unbiased molecular analyses will reveal pathways and ontologies controlled by NRF2, CIS-ETO and their combination in lung neuroendocrine cancers. A primary objective is to test NRF2 inhibitors as strategies to prevent or overcome chemoresistance in SCLC/LCNEC. Aim 2 will test a novel therapeutic approach to block NRF2. VVD-065 is an allosteric molecular glue that results in specific, potent, robust degradation of NRF2, including in cancers harboring select KEAP1 or NFE2L2 mutations. Using a bank of SCLC and LCNEC PDX models along with syngeneic models of SCLC, we will test if VVD-065 sensitizes to CIS-ETO and/or anti-PD1. We will elucidate the impact of NRF2 suppression together with ICI on tumor and immune cells. The results may support near-future clinical trials to overcome or prevent therapy resistance in SCLC/LCNEC. Last, we hypothesize that KEAP1/NFE2L2 mutations will be more prevalent in SCLC after treatment relapse and that new candidate drivers of chemoresistance could be identified using genomic analyses of SCLC samples from therapy treated patients. Currently available genomic data on chemotherapy treated SCLC is scant. The objective of Aim 3 is to perform deep genomic analyses to identify the mutational landscape of treatment-relapsed SCLC. We take advantage of the high fraction of ctDNA in the blood of SCLC patients to perform whole genome sequencing of cell free DNA before and following treatment with chemoimmunotherapy. Using longitudinally collected patient samples clonal analyses will reveal DNA mutations, deletions and gene amplifications associated with therapy resistance. Project Number: 1R01CA305981-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: David MacPherson (+1 co-PI) | Institution: FRED HUTCHINSON CANCER CENTER, SEATTLE, WA | Award Amount: $712,569 | Activity Code: R01 | Study Section: Mechanisms of Cancer Therapeutics B Study Section[MCTB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11391955