Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non-Small Cell Lung Cancers.
Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non-Small Cell Lung Cancers.
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DOI：
10.1158/0008-5472.can-15-3052
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发表时间：
2017-06-01
期刊：
影响因子：
11.2
通讯作者：
Wu LF
中科院分区：
文献类型：
--
作者：
Deb D;Rajaram S;Larsen JE;Dospoy PD;Marullo R;Li LS;Avila K;Xue F;Cerchietti L;Minna JD;Altschuler SJ;Wu LF
肺癌细胞信号转导的癌基因特异性改变已被广泛观察到。在这里，我们研究了这些改变如何影响信号的异质性，并提出了新的治疗策略。我们比较了用TP53、K-RAS和MYC的不同组合系统转化的六个人支气管上皮细胞(HBEC)株的信号变化-非小细胞肺癌(NSCLC)中常见的致癌改变。我们在单细胞分辨率下询问了这些改变如何影响非小细胞肺癌中常见的关键通路的经典读数(β-连环蛋白、Smad2/3、磷酸化STAT3、p65、FOXO1和磷酸化ERK1/2)。所有三种致癌基因改变都需要同时观察到显著的信号变化，在这种情况下出现了显著的异质性。出乎意料的是，我们发现了两个相互排斥的改变亚群：一个是STAT3上调，另一个是Smad2/3下调。用STAT3抑制剂处理消除了上调的STAT3亚群，但留下了大量下调Smad2/3的存活亚群。生物信息学搜索发现，Smad2/3下游的基因BCL6是我们转化的HBEC的一个新的药物可及靶点。在一组NSCLC细胞系和异种移植瘤中，联合使用STAT3和BCL6抑制剂可以显著减少肿瘤细胞的生长。我们得出结论，BCL6是非小细胞肺癌新的治疗靶点，针对常见癌基因和肿瘤抑制基因下游的多个易损性(STAT3和BCL6)的联合治疗可能提供一种有效的方法来克服肿瘤内的异质性。
Oncogene-specific changes in cellular signaling have been widely observed in lung cancer. Here, we investigated how these alterations could affect signaling heterogeneity and suggest novel therapeutic strategies. We compared signaling changes across six human bronchial epithelial cell (HBEC) strains that were systematically transformed with various combinations of TP53, K-RAS, and MYC—oncogenic alterations commonly found in non-small cell lung cancer (NSCLC). We interrogated at single-cell resolution how these alterations could affect classic readouts (β-CATENIN, SMAD2/3, phospho-STAT3, P65, FOXO1 and phospho-ERK1/2) of key pathways commonly affected in NSCLC. All three oncogenic alterations were required concurrently to observe significant signaling changes, and significant heterogeneity arose in this condition. Unexpectedly, we found two mutually exclusive altered subpopulations: one with STAT3 up-regulation and another with SMAD2/3 down-regulation. Treatment with a STAT3 inhibitor eliminated the up-regulated STAT3 subpopulation, but left a large surviving subpopulation with down-regulated SMAD2/3. A bioinformatics search identified BCL6, a gene downstream of SMAD2/3, as a novel pharmacologically accessible target of our transformed HBECs. Combination treatment with STAT3 and BCL6 inhibitors across a panel of NSCLC cell lines and in xenografted tumors significantly reduced tumor cell growth. We conclude that BCL6 is a new therapeutic target in NSCLC and combination therapy that targets multiple vulnerabilities (STAT3 and BCL6) downstream of common oncogenes and tumor suppressors may provide a potent way to defeat intra-tumor heterogeneity.