Targeting BCL-2 family proteins to overcome drug resistance in non-small cell lung cancer

Int J Cancer. 2007 Dec 1;121(11):2387-94. doi: 10.1002/ijc.22977.


Cytotoxic chemotherapies are standard of care for patients suffering from advanced non-small cell lung cancer (NSCLC). However, objective responses are only achieved in 20% of cases and long-term survival is rarely observed. Clinically applied anticancer drugs exert at least some of their activities by inducing apoptosis. A critical step in apoptotic signal transduction is the permeabilization of the mitochondrial outer membrane (MOM), which is regulated by the BCL-2 family of proteins. Hence, therapeutic targeting of BCL-2 proteins is a promising approach to increase the drug-sensitivity of cancers. To this end we have assessed the impact of conditional expression of the proapoptotic multidomain (BH1-2-3) protein BAK, which directly permeabilizes the MOM, and the BH3-mimetic ABT-737, which acts indirectly by derepressing BH1-2-3 proteins, on apoptosis and drug sensitivity of NSCLC cells. Conditionally expressed BAK sensitized resistant NSCLC cells to drug-induced apoptosis. In contrast, ABT-737 was ineffective in those NSCLC cells expressing high levels of the anti-apoptotic MCL-1 protein. Tissue microarray analysis of tumor samples from 84 chemotherapy-naïve NSCLC patients revealed MCL-1 expression in 56% of cases, thus supporting the relevance of this resistance factor in a clinical setting. Enforced expression of the BH3-only protein NOXA, which targets MCL-1, overcame resistance to ABT-737. Moreover, combining conditionally expressed BAK with ABT-737 enhanced apoptosis in NSCLC cells independently of their MCL-1 status. In conclusion, the heterogeneity of apoptosis defects observed in drug-resistant NSCLC demands individually tailored molecular therapies. Targeting the MOM permeabilizer BAK appears to have a broader apoptogenic activity than the BH3-only mimetic ABT-737.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Biphenyl Compounds / pharmacology*
  • Butylated Hydroxytoluene / analogs & derivatives
  • Butylated Hydroxytoluene / metabolism
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line, Tumor
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm* / drug effects
  • Electrophoresis
  • Etoposide / pharmacology
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / metabolism*
  • Nitrophenols / pharmacology*
  • Paclitaxel / pharmacology
  • Permeability
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Signal Transduction
  • Sulfonamides / pharmacology*
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism


  • ABT-737
  • Antineoplastic Agents
  • BAK1 protein, human
  • Biphenyl Compounds
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Nitrophenols
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • bcl-2 Homologous Antagonist-Killer Protein
  • Butylated Hydroxytoluene
  • Etoposide
  • BH 3
  • Doxorubicin
  • Paclitaxel