Sensitizing non-small cell lung cancer to BCL-xL-targeted apoptosis

  • Cell Death Dis. 2018 Sep 24;9(10):986. doi: 10.1038/s41419-018-1040-9.
Qi Shen  1 ,  Jun Li  1  2 ,  Junhua Mai  1 ,  Zhe Zhang  1 ,  Andrew Fisher  1 ,  Xiaoyan Wu  1 ,  Zhaoqi Li  1  2 ,  Maricela R Ramirez  1 ,  Shuqing Chen  3 ,  Haifa Shen  4  5  6
Affiliations
  • 1. Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX, 77030, USA.
  • 2. Xiangya School of Medicine, Central South University, 410008, Changsha, Hunan, China.
  • 3. Department of Drug Metabolism and Drug Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, Zhejiang, China.
  • 4. Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX, 77030, USA. [email protected].
  • 5. Department of Cell and Developmental Biology, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. [email protected].
  • 6. Houston Methodist Cancer Center, Houston, TX, 77030, USA. [email protected].
PMID: 30250075 DOI: 10.1038/s41419-018-1040-9
Abstract

Lung Cancer is the leading cause of death in the United States, with non-small cell lung cancers (NSCLC) accounting for 85% of all cases. By analyzing the expression profile of the pro-apoptotic and anti-apoptotic proteins, we have assigned NSCLCs into two distinct groups. While single agent treatment with the Bcl-2/Bcl-xL/Bcl-W Inhibitor ABT-263 (navitoclax) did not trigger Apoptosis in either group, cells with a moderate to high level of Mcl-1 expression were sensitive to ABT-263 treatment when Mcl-1 expression was suppressed with a gene-specific siRNA. In contrast, those with a low Mcl-1 expression did not undergo Apoptosis upon combination treatment with ABT-263 and Mcl-1 siRNA. Further studies revealed that cells with a low Mcl-1 expression had low mitochondrial priming, and treatment with the chemotherapy drug docetaxel raised the mitochondrial priming level and consequently sensitized cells to ABT-263. These results establish a rationale for molecular profiling and a therapeutic strategy to treat NSCLC patients with pro-apoptotic anti-cancer drugs based on their Mcl-1 expression level.

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