BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents.
Cancer cells exhibit many abnormal phenotypes that induce apoptotic signaling via the intrinsic, or mitochondrial, pathway. That cancer cells nonetheless survive implies that they select for blocks in apoptosis. Identifying cancer-specific apoptotic blocks is necessary to rationally target them. Using a panel of 18 lymphoma cell lines, we show that a strategy we have developed, BH3 profiling, can identify apoptotic defects in cancer cells and separate them into three main classes based on position in the apoptotic pathway. BH3 profiling identifies cells that require BCL-2 for survival and predicts sensitivity to the BCL-2 antagonist ABT-737. BCL-2 dependence correlates with high levels of proapoptotic BIM sequestered by BCL-2. Strikingly, BH3 profiling can also predict sensitivity to conventional chemotherapeutic agents like etoposide, vincristine, and adriamycin.
Deng
Jing
J
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Carlson
Nicole
N
Takeyama
Kunihiko
K
Dal Cin
Paola
P
Shipp
Margaret
M
Letai
Anthony
A
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000494:pharmacology
C501332:ABT-737; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds; D008565:Membrane Proteins; D009596:Nitrophenols; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin