ABL allosteric inhibitors synergize with statins to enhance apoptosis of metastatic lung cancer cells.
ABL allosteric inhibitors synergize with statins to enhance apoptosis of metastatic lung cancer cells.
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DOI：
10.1016/j.celrep.2021.109880
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发表时间：
2021-10-26
期刊：
影响因子：
8.8
通讯作者：
Pendergast AM
中科院分区：
文献类型：
--
作者：
Luttman JH;Hoj JP;Lin KH;Lin J;Gu JJ;Rouse C;Nichols AG;MacIver NJ;Wood KC;Pendergast AM
针对线粒体代谢已成为癌症患者的一种治疗选择。 ABL 酪氨酸激酶促进转移，增强的 ABL 信号传导与肺腺癌患者的不良预后相关。在这里，我们证明 ABL 激酶变构抑制剂会损害线粒体完整性并降低氧化磷酸化。为了确定增强这种表型的代谢脆弱性，我们利用 CRISPR/Cas9 功能丧失筛选，并确定了 HMG-CoA 还原酶（甲羟戊酸途径的限速酶和他汀类药物治疗的靶点）作为 ABL 抑制的最高分敏化剂。 ABL 变构抑制剂和他汀类药物的联合治疗以协同方式降低体外转移性肺癌细胞的存活率。值得注意的是，肺癌脑转移和治疗耐药小鼠模型的联合治疗会损害转移定植，同时增加动物存活率。因此，代谢联合疗法可能有效减少转移生长，从而提高晚期肺癌患者的生存率。肿瘤中的代谢重编程是一种适应，会产生可用于开发新疗法的漏洞。卢特曼等人在这里。确定 ABL 变构抑制剂和亲脂性他汀类药物之间的协同作用，以损害转移性肺癌细胞的生长和定植，从而提高晚期疾病小鼠模型的存活率。
Targeting mitochondrial metabolism has emerged as a treatment option for cancer patients. The ABL tyrosine kinases promote metastasis, and enhanced ABL signaling is associated with a poor prognosis in lung adenocarcinoma patients. Here we show that ABL kinase allosteric inhibitors impair mitochondrial integrity and decrease oxidative phosphorylation. To identify metabolic vulnerabilities that enhance this phenotype, we utilized a CRISPR/Cas9 loss-of-function screen and identified HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway and target of statin therapies, as a top-scoring sensitizer to ABL inhibition. Combination treatment with ABL allosteric inhibitors and statins decreases metastatic lung cancer cell survival in vitro in a synergistic manner. Notably, combination therapy in mouse models of lung cancer brain metastasis and therapy resistance impairs metastatic colonization with a concomitant increase in animal survival. Thus, metabolic combination therapy might be effective to decrease metastatic outgrowth, leading to increased survival for lung cancer patients with advanced disease. Metabolic reprogramming in tumors is an adaptation that generates vulnerabilities that can be exploited for developing new therapies. Here Luttman et al. identify synergism between ABL allosteric inhibitors and lipophilic statins to impair metastatic lung cancer cell outgrowth and colonization, leading to increased survival in mouse models of advanced disease.
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影响因子：
3.7
作者：
Gu JJ;Hoj J;Rouse C;Pendergast AM
通讯作者：
Pendergast AM
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
8
作者：
Gil-Henn, H.;Patsialou, A.;Wang, Y.;Warren, M. S.;Condeelis, J. S.;Koleske, A. J.
通讯作者：
Koleske, A. J.
影响因子：
50.5
作者：
Dy, GK;Miller, AA;Adjei, AA
通讯作者：
Adjei, AA
影响因子：
4.6
作者：
Chou, Cheng-Wei;Lin, Ching-Heng;Sher, Yuh-Pyng
通讯作者：
Sher, Yuh-Pyng