title: PUMA and BIM are required for oncogene inactivation-induced apoptosis.
abstract: The clinical efficacy of tyrosine kinase inhibitors supports the dependence of distinct subsets of cancers on specific driver mutations for survival, a phenomenon called "oncogene addiction." We demonstrate that PUMA and BIM are the key apoptotic effectors of tyrosine kinase inhibitors in breast cancers with amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) and lung cancers with epidermal growth factor receptor (EGFR) mutants. The BH3 domain containing proteins BIM and PUMA can directly activate the proapoptotic proteins BAX and BAK to permeabilize mitochondria, leading to caspase activation and apoptosis. We delineated the signal transduction pathways leading to the induction of BIM and PUMA by tyrosine kinase inhibitors. Inhibition of the mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway caused increased abundance of BIM, whereas antagonizing the phosphoinositide 3-kinase (PI3K)-AKT pathway triggered nuclear translocation of the FOXO transcription factors, which directly activated the PUMA promoter. In a mouse breast tumor model, the abundance of PUMA and BIM was increased after inactivation of HER2. Moreover, deficiency of Bim or Puma impaired caspase activation and reduced tumor regression caused by inactivation of HER2. Similarly, deficiency of Puma impeded the regression of EGFR(L858R)-driven mouse lung tumors upon inactivation of the EGFR-activating mutant. Overall, our study identified PUMA and BIM as the sentinels that interconnect kinase signaling networks and the mitochondrion-dependent apoptotic program, which offers therapeutic insights for designing novel cell death mechanism-based anticancer strategies.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Bean
authors.forename: Yogesh Tengarai
authors.initials: YT
authors.lastname: Ganesan
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Dong
authors.forename: Shugaku
authors.initials: S
authors.lastname: Takeda
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.forename: Po M
authors.initials: PM
authors.lastname: Chan
authors.forename: Yafen
authors.initials: Y
authors.lastname: Huang
authors.forename: Lewis A
authors.initials: LA
authors.lastname: Chodosh
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Zambetti
authors.forename: James J-D
authors.initials: JJ
authors.lastname: Hsieh
authors.forename: Emily H-Y
authors.initials: EH
authors.lastname: Cheng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D000077341:Lapatinib; D020935:MAP Kinase Signaling System / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009596:Nitrophenols / Q000494:pharmacology; D009857:Oncogenes / Q000235:genetics / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds; D066246:ErbB Receptors; D000077341:Lapatinib; D008565:Membrane Proteins; D009596:Nitrophenols; D010879:Piperazines; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D013449:Sulfonamides; C501332:ABT-737; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; C000606776:Bcl2l11 protein, mouse; C508053:ERBB2 protein, human