KEAP1/NFE2L2 Mutations Predict Lung Cancer Radiation Resistance That Can Be Targeted by Glutaminase Inhibition

Abstract

Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in tumors with KEAP1/NFE2L2 mutations, indicating that they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1 -mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our fi ndings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations. SIGNIFICANCE:This study shows that mutations in KEAP1 and NFE2L2 predict for LR after radiotherapy but not surgery in patients with NSCLC. Approximately half of all LRs are associated with these mutations and glutaminase inhibition may allow personalized radiosensitization of KEAP1/NFE2L2mutant tumors.

The Impact of Durvalumab on Local-Regional Control in Stage III NSCLCs Treated With Chemoradiation and on KEAP1-NFE2L2-Mutant Tumors

“…That study found that KEAP1-NFE2L2-mutant tumors are at an increased risk of local-regional failure, with two-year recurrence rates of 50% versus 17% in tumors without KEAP1-NFE2L2 mutations. 8 Consistent with these data, we also found a significantly greater incidence of localregional failure among KEAP1-NFE2L2-mutated tumors after cCRT alone, further validating this subgroup to be chemoradiation resistant.…”

“…Consistent with other reports, we found patients with KEAP1-NFE2L2-mutated tumors, a chemoradiation-resistant phenotype, to have worse local-regional control outcomes when treated with cCRT alone. 8 Nevertheless, the influence of KEAP1-NFE2L2 mutation status on locoregional control in patients with NSCLC treated with cCRT and durvalumab has not been previously characterized, and we did not find KEAP1-NFE2L2-mutated tumors to have worse control outcomes when treated with cCRT and durvalumab. Furthermore, we found treatment with cCRT and durvalumab to result in a striking improvement in local-regional control in patients with KEAP1-NFE2L2-mutant tumors compared with cCRT alone.…”

“…Age, sex, stage, tumor volume, smoking history, Tumor Histology, Eastern Cooperative Oncology Group (ECOG) performance status, programmed death-ligand 1 (PD-L1) expression, KRAS, STK11, PBRM1, SMARCA4 mutational status, KEAP1-NFE2L2 mutational status, and time to durvalumab start from end of radiotherapy were collected. Mutations in KEAP1 and NFE2L2 were considered as one group as previously described 8 given that they result in the same phenotype of NFE2L2 overexpression. 18 Baseline characteristics between patients with and without KEAP1-NFE2L2 tumor mutations were compared using the chi-square test, Fisher's exact, or the Wilcoxon test.…”

“…18,25 Mutations in KEAP1-NFE2L2 genes can lead to NFE2L2 overexpression and thereby protect cancer cells from the effects of radiation and cytotoxic chemotherapy. 7,8,11 Work by Binkley et al 8 established the predictive value of KEAP1-NFE2L2 mutations on radiation resistance in a series of 232 patients with NSCLC, of whom 47 were treated with cCRT. That study found that KEAP1-NFE2L2-mutant tumors are at an increased risk of local-regional failure, with two-year recurrence rates of 50% versus 17% in tumors without KEAP1-NFE2L2 mutations.…”

“…5,6 Mutations in the KEAP1-NFE2L2 pathway, which plays a key role in cellular stress response, have been postulated as a major mechanism behind chemoradiation treatment failures in NSCLC. 7,8 Mutations in either KEAP1 or NFE2L2 are found in approximately 25% of NSCLCs and are associated with potentially half of all local-regional failures, presumably by interfering with chemotherapy and radiation-induced DNA damage. [9][10][11][12] The association between KEAP1-NFE2L2 mutations and outcomes in patients treated with concurrent chemoradiation and durvalumab remains unknown as previous studies evaluating the impact of these mutations on immunotherapy outcomes have been limited to patients with advanced NSCLC and have had conflicting results.…”