Targeting BCL-2 family proteins to overcome drug resistance in non-small cell lung cancer.
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.
Wesarg
Emmanuelle
E
Gene Therapy Laboratory, Johannes Gutenberg University, Mainz, Germany.
Hoffarth
Sandra
S
Wiewrodt
Rainer
R
Kröll
Monika
M
Biesterfeld
Stefan
S
Huber
Christoph
C
Schuler
Martin
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002084:Butylated Hydroxytoluene / Q000031:analogs & derivatives / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004586:Electrophoresis; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology; D010539:Permeability; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
C501332:ABT-737; D000970:Antineoplastic Agents; C494772:BAK1 protein, human; D001713:Biphenyl Compounds; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D002084:Butylated Hydroxytoluene; D005047:Etoposide; C006008:BH 3; D004317:Doxorubicin; D017239:Paclitaxel