Heightening Energetic Stress Selectively Targets LKB1-Deficient Non-Small Cell Lung Cancers.
Heightening Energetic Stress Selectively Targets LKB1-Deficient Non-Small Cell Lung Cancers.
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DOI：
10.1158/0008-5472.can-15-0797
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发表时间：
2015-11-15
期刊：
影响因子：
11.2
通讯作者：
Shackelford DB
中科院分区：
文献类型：
--
作者：
Momcilovic M;McMickle R;Abt E;Seki A;Simko SA;Magyar C;Stout DB;Fishbein MC;Walser TC;Dubinett SM;Shackelford DB
LKB1 肿瘤抑制因子的失活是非小细胞肺癌 (NSCLC) 中的常见事件，导致哺乳动物雷帕霉素靶复合物 1 (mTORC1) 的激活以及对代谢应激诱导剂苯乙双胍的敏感性。在这项研究中，我们探索了苯乙双胍与 mTOR 催化激酶抑制剂 MLN0128 的组合使用，作为 LKB1 和 KRAS 基因共突变 NSCLC 的治疗策略。非小细胞肺癌是一种遗传和病理异质性疾病，可引起不同组织学的肺部肿瘤，包括腺癌 (ADC) 和鳞状细胞癌 (SCC)。我们证明，苯乙双胍与 MLN0128 联合在 KRAS/LKB1 突变人类细胞系和同时发育 ADC 和 SCC 的 NSCLC 基因工程小鼠模型中诱导显着的治疗反应。具体来说，我们发现 KRAS/LKB1 突变肺 ADC 对苯乙双胍 + MLN0128 治疗反应强烈，但由于通过调节 AKT-GSK 信号轴获得了对 mTOR 抑制的抗性，SCC 对 MLN0128 单一或联合治疗的反应更加减弱。 mTOR 抑制剂和 AKT 抑制剂 MK2206 的组合使用可有效抑制鳞状肺肿瘤的生长和活力，从而提供克服耐药性的有效策略。总而言之，我们的研究结果定义了新的个性化治疗策略，可以快速转化为治疗 KRAS/LKB1 突变腺癌和鳞状细胞肿瘤的临床应用。
Inactivation of the LKB1 tumor suppressor is a frequent event in non-small cell lung carcinoma (NSCLC) leading to the activation of mammalian target of rapamycin complex 1 (mTORC1) and sensitivity to the metabolic stress inducer phenformin. In this study, we explored the combinatorial use of phenformin with the mTOR catalytic kinase inhibitor MLN0128 as a treatment strategy for NSCLC bearing co-mutations in the LKB1 and KRAS genes. NSCLC is a genetically and pathologically heterogeneous disease, giving rise to lung tumors of varying histologies that include adenocarcinomas (ADCs) and squamous cell carcinomas (SCCs). We demonstrate that phenformin in combination with MLN0128 induced a significant therapeutic response in KRAS/LKB1 mutant human cell lines and genetically engineered mouse models of NSCLC that develop both ADCs and SCCs. Specifically, we found that KRAS/LKB1 mutant lung ADCs responded strongly to phenformin + MLN0128 treatment, but the response of SCCs to single or combined treatment with MLN0128 was more attenuated due to acquired resistance to mTOR inhibition through modulation of the AKT-GSK signaling axis. Combinatorial use of the mTOR inhibitor and AKT inhibitor MK2206 robustly inhibited the growth and viability of squamous lung tumors thus providing an effective strategy to overcome resistance. Taken together, our findings define new personalized therapeutic strategies that may be rapidly translated into clinical use for the treatment of KRAS/LKB1 mutant adenocarcinomas and squamous cell tumors.