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  • Recently the KEAP NFE L pathway has been


    Recently, the KEAP1-NFE2L2 pathway has been implicated in the development of EGFR TKI resistance. The KEAP1-NFE2L2 pathway plays a key role in cellular stress response by driving Pifithrin-α (PFTα) of anti-free radical defense genes and detoxification enzymes. When a cell is stressed, key residues in the KEAP1 protein are oxidized, rendering it unable to bind to the transcription factor NFE2L2 (also known as NRF2). NFE2L2 then migrates to the nucleus and is able to transcribe its targets, leading to expression of genes containing antioxidant response elements (ARE) in their promoters [6]. Mutations in KEAP1 or NFE2L2 occur in approximately 20–25% of lung adenocarcinomas [7,8] and lead to constitutive activation of NFE2L2. This results in pro-survival signals [9], resistance to chemotherapy in KRAS mutant tumors [10], and radioresistance [11]. Pre-clinical data suggest that the KEAP1-NFE2L2 pathway may play an important role in EGFR-TKI resistance [12,13]. Early studies have shown that NFE2L2 pathway is activated not only by KEAP1, but also through the EGFR signaling pathway and mutations in the KEAP1 pathway significantly reduce sensitivity to EGFR TKIs in vitro and enhance tumor aggressiveness [12,14]. Therefore, we hypothesized that patients with EGFR and KEAP1/NFE2L2 mutated NSCLC will have shortened time to treatment failure on EGFR TKI compared with their KEAP1/NFE2L2 wild-type (WT) counterparts.
    Materials and methods Stage IV NSCLC patients who had tumor specimens analyzed using the Stanford Solid Tumor Actionable Mutation Panel (STAMP) [15] as part of routine clinical care between 2015 and 2018, and who provided their consent to participate in a molecular analysis study approved by the Stanford University Institutional Review Board, were included. STAMP was performed on tumor specimens, the timing of which was determined by the treating clinician. Patients were selected if they had biopsy-proven stage IV NSCLC, sensitizing EGFR driver mutations, and were treated with an EGFR TKI. Patients with recurrent disease after treatment for early stage disease could not have received EGFR TKI in the adjuvant setting during their initial treatment. Patients who were lost to follow up or who elected not to receive treatment were excluded. Demographic information including age at cancer diagnosis, gender, smoking history (former, current, never smoker) and race/ethnicity were abstracted from each patient’s medical record. Date of initiation of therapy was defined as the first day of TKI administration. Date of progression was defined as the start of subsequent treatment or death, whichever came first. Time to treatment failure (TTF) was calculated from the date of therapy initiation to the date of progression as defined by the treating clinician. Overall survival (OS) was calculated by subtracting the date of diagnosis from the date of death, also reported in months. Patients who died before radiographic reassessment were considered to have OS events. For the control cohort, all patients with EGFR mutations with available next generation sequencing from 2015 to 2018 who were wild type for KEAP1/NFE2L2/CUL3 mutations were abstracted. Patients were matched to the KEAP1/NFE2L2/CUL3 cohort in a ratio of 1:3 on the basis of gender, age at diagnosis, EGFR TKI, smoking history (never, former, current) and race/ethnicity.
    Results We identified a cohort of 228 metastatic EGFR mutant NSCLC patients who had undergone tumor genotyping using the Stanford Solid Tumor Actionable Mutation Panel. Of these patients, 17 (7%) had mutations in KEAP1/NFE2L2/CUL3. Nine patients received first line EGFR TKI with erlotinib (n = 8) or osimertinib (n = 1). Of the eight patients who did not receive front line TKI therapies, three went on to receive second line TKI and were included in the analysis. Out of twelve patients, 4 had mutations in KEAP1, 7 in NFE2L2, and 1 in CUL3 (Cohort mutations in Supplemental Table 1). Cohort characteristics included average age of 68 years old, and a predominance of females (67%), Asians (67%) and never-smokers (83%). There was no significant difference between the KEAP1/NFE2L2/CUL3 mutated cohort and control cohort in regards to age, gender, smoking status, race, histology or first line therapy (Table 1).