Dynamic BH3 profiling identifies active BH3 mimetic combinations in non-small cell lung cancer.
Dynamic BH3 profiling identifies active BH3 mimetic combinations in non-small cell lung cancer.
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DOI：
10.1038/s41419-021-04029-4
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发表时间：
2021-07-27
影响因子：
9
通讯作者：
Letai A
中科院分区：
文献类型：
--
作者：
Potter DS;Du R;Bhola P;Bueno R;Letai A
常规化疗在肿瘤治疗中仍有很大的作用，合理构建与常规化疗的联合方案仍是当务之急。通过动态BH 3谱（DBP）测量的药物诱导的线粒体凋亡引发已在多种癌症中显示，以鉴定促进体内凋亡的药物。因此，我们假设我们可以使用DBP来鉴定使癌症对常规化疗更敏感的药物。我们发现，靶向药物，增加非小细胞肺癌（NSCLC）肿瘤细胞的启动，导致体外化疗的敏感性增加。为了评估增加引发的靶向药物是否也可以增强细胞毒性药物在体内的功效，我们在PC 9异种移植小鼠模型中进行了功效研究。拮抗BCL-xL、BCL-w和BCL-2的BH 3模拟物navitoclax在体外和体内一致地引发NSCLC肿瘤。选择性拮抗BCL-2的BH 3模拟物维奈托克则没有。与任一单药相比，联合使用navitoclax和依托泊苷显著降低了肿瘤负荷，而在依托泊苷中加入维奈托克对肿瘤负荷没有影响。接下来，我们评估了来自临床相关肿瘤学联合筛查（CROCS）的药物对原发性患者NSCLC肿瘤细胞的致敏作用。结果首次证实了navitoclax对BCL-xL抑制在引发原发性NSCLC肿瘤细胞中的效用，并鉴定了进一步引发的组合。这证明了DBP可用作功能性精准医学工具的原理，以合理构建包括BH 3模拟物的组合药物方案，用于实体瘤如NSCLC。
Conventional chemotherapy is still of great utility in oncology and rationally constructing combinations with it remains a top priority. Drug-induced mitochondrial apoptotic priming, measured by dynamic BH3 profiling (DBP), has been shown in multiple cancers to identify drugs that promote apoptosis in vivo. We therefore hypothesized that we could use DBP to identify drugs that would render cancers more sensitive to conventional chemotherapy. We found that targeted agents that increased priming of non-small cell lung cancer (NSCLC) tumor cells resulted in increased sensitivity to chemotherapy in vitro. To assess whether targeted agents that increase priming might enhance the efficacy of cytotoxic agents in vivo as well, we carried out an efficacy study in a PC9 xenograft mouse model. The BH3 mimetic navitoclax, which antagonizes BCL-xL, BCL-w, and BCL-2, consistently primed NSCLC tumors in vitro and in vivo. The BH3 mimetic venetoclax, which electively antagonizes BCL-2, did not. Combining navitoclax with etoposide significantly reduced tumor burden compared to either single agent, while adding venetoclax to etoposide had no effect on tumor burden. Next, we assessed priming of primary patient NSCLC tumor cells on drugs from a clinically relevant oncology combination screen (CROCS). Results confirmed for the first time the utility of BCL-xL inhibition by navitoclax in priming primary NSCLC tumor cells and identified combinations that primed further. This is a demonstration of the principle that DBP can be used as a functional precision medicine tool to rationally construct combination drug regimens that include BH3 mimetics in solid tumors like NSCLC.
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影响因子：
11.2
作者：
Terai H;Kitajima S;Potter DS;Matsui Y;Quiceno LG;Chen T;Kim TJ;Rusan M;Thai TC;Piccioni F;Donovan KA;Kwiatkowski N;Hinohara K;Wei G;Gray NS;Fischer ES;Wong KK;Shimamura T;Letai A;Hammerman PS;Barbie DA
通讯作者：
Barbie DA
影响因子：
4.8
作者：
Brumatti, Gabriela;Sheridan, Clare;Martin, Seamus J.
通讯作者：
Martin, Seamus J.
影响因子：
50.3
作者：
Certo, Michael;Moore, Victoria Del Gaizo;Letai, Anthony
通讯作者：
Letai, Anthony
影响因子：
11.2
作者：
Daniel VC;Marchionni L;Hierman JS;Rhodes JT;Devereux WL;Rudin CM;Yung R;Parmigiani G;Dorsch M;Peacock CD;Watkins DN
通讯作者：
Watkins DN
影响因子：
64.8
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM