Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling.
Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling.
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DOI：
10.1038/s42003-023-04618-3
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发表时间：
2023-03-10
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
--
作者：
SETD2是一种肿瘤抑制因子，在几种癌症类型中经常失活。SETD2失活促进癌症的机制尚不清楚，这些肿瘤中是否存在可靶向的脆弱性也尚不清楚。在kras驱动的肺腺癌小鼠模型中，我们发现mtorc1相关基因表达程序升高，氧化代谢和蛋白质合成功能水平升高，这是Setd2失活的显著后果。阻断氧化呼吸和mTORC1信号通路可消除高速率的肿瘤细胞增殖和肿瘤生长，特别是在setd2缺陷肿瘤中。我们的数据表明SETD2缺陷是对临床可操作的靶向氧化呼吸和mTORC1信号治疗的敏感性的功能标记。在kras驱动的肺腺癌小鼠模型中，SETD2失活导致mTORC1信号、氧化代谢和蛋白质合成升高，有助于理解SETD2缺陷如何驱动早期和广泛的肿瘤生长。
SETD2 is a tumor suppressor that is frequently inactivated in several cancer types. The mechanisms through which SETD2 inactivation promotes cancer are unclear, and whether targetable vulnerabilities exist in these tumors is unknown. Here we identify heightened mTORC1-associated gene expression programs and functionally higher levels of oxidative metabolism and protein synthesis as prominent consequences of Setd2 inactivation in KRAS-driven mouse models of lung adenocarcinoma. Blocking oxidative respiration and mTORC1 signaling abrogates the high rates of tumor cell proliferation and tumor growth specifically in SETD2-deficient tumors. Our data nominate SETD2 deficiency as a functional marker of sensitivity to clinically actionable therapeutics targeting oxidative respiration and mTORC1 signaling. SETD2 inactivation leads to heightened mTORC1 signaling, oxidative metabolism and protein synthesis in KRAS-driven mouse models of lung adenocarcinoma, contributing to the understanding of how SETD2 deficiency drives early and widespread tumor growth.
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