title: Systems analysis of BCL2 protein family interactions establishes a model to predict responses to chemotherapy.
abstract: Apoptotic desensitization is a hallmark of cancer cells, but present knowledge of molecular systems controlling apoptosis has yet to provide significant prognostic insights. Here, we report findings from a systems study of the intrinsic pathway of apoptosis by BCL2 family proteins and clinical translation of its findings into a model with applications in colorectal cancer (CRC). By determining absolute protein quantifications in CRC cells and patient tumor samples, we found that BAK and BAX were expressed more highly than their antiapoptotic inhibitors. This counterintuitive finding suggested that sole inhibition of effector BAX and BAK could not be sufficient for systems stability in nonstressed cells. Assuming a model of direct effector activation by BH3-only proteins, we calculated that the amount of stress-induced BH3-only proteins required to activate mitochondrial apoptosis could predict individual death responses of CRC cells to 5-fluorouracil/oxaliplatin. Applying this model predictor to protein profiles in tumor and matched normal tissue samples from 26 patients with CRCs, we found that differences in protein quantities were sufficient to model the increased tumor sensitivity to chemotherapy compared with normal tissue. In addition, these differences were sufficient to differentiate clinical responders from nonresponders with high confidence. Applications of our model, termed DR_MOMP, were used to assess the impact of apoptosis-sensitizing drugs in lowering the necessary dose of state-of-the-art chemotherapy in individual patients. Together, our findings offer a ready clinical tool with the potential to tailor chemotherapy to individual patients.
authors: Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors: Andreas U
authors: AU
authors: Lindner
authors: Caoimhín G
authors: CG
authors: Concannon
authors: Gerhardt J
authors: GJ
authors: Boukes
authors: Mary D
authors: MD
authors: Cannon
authors: Fabien
authors: F
authors: Llambi
authors: Deborah
authors: D
authors: Ryan
authors: Karen
authors: K
authors: Boland
authors: Joan
authors: J
authors: Kehoe
authors: Deborah A
authors: DA
authors: McNamara
authors: Frank
authors: F
authors: Murray
authors: Elaine W
authors: EW
authors: Kay
authors: Suzanne
authors: S
authors: Hector
authors: Douglas R
authors: DR
authors: Green
authors: Heinrich J
authors: HJ
authors: Huber
authors: Jochen H M
authors: JH
authors: Prehn
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019295:Computational Biology; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D040081:Protein Array Analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013597:Systems Analysis; D016896:Treatment Outcome; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein