Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma
Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma
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DOI：
10.1038/s41467-019-12164-y
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发表时间：
2019-09-13
影响因子：
16.6
通讯作者：
Sutherland, Kate D.
中科院分区：
文献类型：
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作者：
Best, Sarah A.;Ding, Sheryl;Sutherland, Kate D.
KRAS癌蛋白是33%的肺腺癌(LUAD)的关键驱动因素，由于其不可药物的性质，一直是一个难以捉摸的临床靶点。寻求通过常见的共生突变来识别依赖关系，以更有效地针对KRAS突变的肺癌。大约20%的KRAS突变体LUAD携带Keap1的功能缺失突变，Keap1是抗氧化反应转录因子NFE2L2/NRF2的负调控因子。我们证明Keapl缺陷的Kras(G)(12D)肺癌起源于细支气管细胞，在起源于肺泡细胞的肿瘤中观察到缺乏促肿瘤的巨噬细胞。Keap1的缺失激活了磷酸戊糖途径，通过6-AN抑制该途径可抑制肿瘤生长。这些研究强调了针对这一独特的KRAS突变LUAD癌症亚群的替代治疗方法。
The KRAS oncoprotein, a critical driver in 33% of lung adenocarcinoma (LUAD), has remained an elusive clinical target due to its perceived undruggable nature. The identification of dependencies borne through common co-occurring mutations are sought to more effectively target KRAS-mutant lung cancer. Approximately 20% of KRAS-mutant LUAD carry loss-offunction mutations in KEAP1, a negative regulator of the antioxidant response transcription factor NFE2L2/NRF2. We demonstrate that Keapl-deficient Kras(G)(12D) lung tumors arise from a bronchiolar cell-of-origin, lacking pro-tumorigenic macrophages observed in tumors originating from alveolar cells. Keap1 loss activates the pentose phosphate pathway, inhibition of which, using 6-AN, abrogated tumor growth. These studies highlight alternative therapeutic approaches to specifically target this unique subset of KRAS-mutant LUAD cancers.