KEAP1/NFE2L2 Mutations Predict Lung Cancer Radiation Resistance That Can Be Targeted by Glutaminase Inhibition.
KEAP1/NFE2L2 Mutations Predict Lung Cancer Radiation Resistance That Can Be Targeted by Glutaminase Inhibition.
复制标题
KEAP1/NFE2L2突变预测肺癌抑制性可以通过谷氨酰胺酶抑制作用。
DOI：
10.1158/2159-8290.cd-20-0282
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发表时间：
2020-12
期刊：
影响因子：
28.2
通讯作者：
Diehn M
中科院分区：
文献类型：
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作者：
Binkley MS;Jeon YJ;Nesselbush M;Moding EJ;Nabet BY;Almanza D;Kunder C;Stehr H;Yoo CH;Rhee S;Xiang M;Chabon JJ;Hamilton E;Kurtz DM;Gojenola L;Owen SG;Ko RB;Shin JH;Maxim PG;Lui NS;Backhus LM;Berry MF;Shrager JB;Ramchandran KJ;Padda SK;Das M;Neal JW;Wakelee HA;Alizadeh AA;Loo BW Jr;Diehn M
由于缺乏突变与结果的关联，局部非小细胞肺癌 (NSCLC) 中不常规进行肿瘤基因分型。在这里，我们连续分析了 232 名局部 NSCLC 患者，并证明 KEAP1 和 NFE2L2 突变可预测放疗后局部复发 (LR) 的高发生率，但不能预测手术后的高局部复发率 (LR)。一半的 LR 发生在 KEAP1/NFE2L2 突变肿瘤中，表明它们是临床放射抗性的主要分子驱动因素。接下来，我们对放疗队列中的 KEAP1/NFE2L2 突变进行功能评估，并证明只有致病性突变与放射抗性相关。此外，NFE2L2 靶基因的表达并不能预测 LR，这强调了肿瘤基因分型的实用性。最后，我们发现，谷氨酰胺酶抑制通过耗尽谷胱甘肽并增加辐射诱导的 DNA 损伤，优先使 KEAP1 突变细胞对放射敏感。我们的研究结果表明，KEAP1/NFE2L2 突变的基因分型可以促进治疗个体化，并为克服这些突变带来的放射抗性提供潜在的策略。
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 KEAP1/NFE2L2 mutation tumors, indicating 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 findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations.