title: BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors.
abstract: Cancers with specific genetic mutations are susceptible to selective kinase inhibitors. However, there is a wide spectrum of benefit among cancers harboring the same sensitizing genetic mutations. Herein, we measured apoptotic rates among cell lines sharing the same driver oncogene following treatment with the corresponding kinase inhibitor. There was a wide range of kinase inhibitor-induced apoptosis despite comparable inhibition of the target and associated downstream signaling pathways. Surprisingly, pretreatment RNA levels of the BH3-only pro-apoptotic BIM strongly predicted the capacity of EGFR, HER2, and PI3K inhibitors to induce apoptosis in EGFR-mutant, HER2-amplified, and PIK3CA-mutant cancers, respectively, but BIM levels did not predict responsiveness to standard chemotherapies. Furthermore, BIM RNA levels in EGFR-mutant lung cancer specimens predicted response and duration of clinical benefit from EGFR inhibitors. These findings suggest assessment of BIM levels in treatment-naïve tumor biopsies may indicate the degree of benefit from single-agent kinase inhibitors in multiple oncogene-addiction paradigms.
authors.affiliation: Massachusetts General Hospital Cancer Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02129, USA.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Faber
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Corcoran
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ebi
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.forename: Belinda A
authors.initials: BA
authors.lastname: Waltman
authors.forename: Euiheon
authors.initials: E
authors.lastname: Chung
authors.forename: Joao
authors.initials: J
authors.lastname: Incio
authors.forename: Subba R
authors.initials: SR
authors.lastname: Digumarthy
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Pollack
authors.forename: Youngchul
authors.initials: Y
authors.lastname: Song
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.forename: Eugene
authors.initials: E
authors.lastname: Lifshits
authors.forename: Sylvie
authors.initials: S
authors.lastname: Roberge
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Coffman
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.forename: Henry L
authors.initials: HL
authors.lastname: Gómez
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.forename: Miguel N
authors.initials: MN
authors.lastname: Rivera
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D015331:Cohort Studies; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; D066246:ErbB Receptors; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C000606775:BCL2L11 protein, human; C494814:BID protein, human; C000606776:Bcl2l11 protein, mouse; C512478:EGFR protein, human; C508053:ERBB2 protein, human