dc.contributor.author | Faber, Anthony C. | |
dc.contributor.author | Costa, Carlotta | |
dc.contributor.author | Dastur, Anahita | |
dc.contributor.author | Gomez-Caraballo, Maria | |
dc.contributor.author | Robbins, Rebecca | |
dc.contributor.author | Wagner, Bethany L. | |
dc.contributor.author | Rideout, William M. | |
dc.contributor.author | Jakubik, Charles T. | |
dc.contributor.author | Ham, Jungoh | |
dc.contributor.author | Edelman, Elena J. | |
dc.contributor.author | Ebi, Hiromichi | |
dc.contributor.author | Yeo, Alan T. | |
dc.contributor.author | Hata, Aaron N. | |
dc.contributor.author | Song, Youngchul | |
dc.contributor.author | Patel, Neha U. | |
dc.contributor.author | March, Ryan J. | |
dc.contributor.author | Tam, Ah Ting | |
dc.contributor.author | Milano, Randy J. | |
dc.contributor.author | Boisvert, Jessica L. | |
dc.contributor.author | Hicks, Mark A. | |
dc.contributor.author | Elmiligy, Sarah | |
dc.contributor.author | Malstrom, Scott E. | |
dc.contributor.author | Rivera, Miguel N. | |
dc.contributor.author | Harada, Hisashi | |
dc.contributor.author | Windle, Brad E. | |
dc.contributor.author | Ramaswamy, Sridhar | |
dc.contributor.author | Benes, Cyril H. | |
dc.contributor.author | Engelman, Jeffrey A. | |
dc.contributor.author | Farago, Anna | |
dc.contributor.author | Malstrom, Scott E. | |
dc.contributor.author | Jacks, Tyler E | |
dc.date.accessioned | 2015-09-08T18:19:25Z | |
dc.date.available | 2015-09-08T18:19:25Z | |
dc.date.issued | 2015-03 | |
dc.date.submitted | 2014-07 | |
dc.identifier.issn | 0027-8424 | |
dc.identifier.issn | 1091-6490 | |
dc.identifier.uri | http://hdl.handle.net/1721.1/98407 | |
dc.description.abstract | BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC. | en_US |
dc.description.sponsorship | United States. Dept. of Defense (Grant W81-XWH-13-1-0323) | en_US |
dc.description.sponsorship | National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051) | en_US |
dc.language.iso | en_US | |
dc.publisher | National Academy of Sciences (U.S.) | en_US |
dc.relation.isversionof | http://dx.doi.org/10.1073/pnas.1411848112 | en_US |
dc.rights | Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. | en_US |
dc.source | National Academy of Sciences (U.S.) | en_US |
dc.title | Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer | en_US |
dc.type | Article | en_US |
dc.identifier.citation | Faber, Anthony C., Anna F. Farago, Carlotta Costa, Anahita Dastur, Maria Gomez-Caraballo, Rebecca Robbins, Bethany L. Wagner, et al. “Assessment of ABT-263 Activity Across a Cancer Cell Line Collection Leads to a Potent Combination Therapy for Small-Cell Lung Cancer.” Proc Natl Acad Sci USA 112, no. 11 (March 3, 2015): E1288–E1296. | en_US |
dc.contributor.department | Koch Institute for Integrative Cancer Research at MIT | en_US |
dc.contributor.mitauthor | Farago, Anna | en_US |
dc.contributor.mitauthor | Robbins, Rebecca | en_US |
dc.contributor.mitauthor | Wagner, Bethany L. | en_US |
dc.contributor.mitauthor | Rideout, William M. | en_US |
dc.contributor.mitauthor | Elmiligy, Sarah | en_US |
dc.contributor.mitauthor | Malstrom, Scott E. | en_US |
dc.contributor.mitauthor | Jacks, Tyler E. | en_US |
dc.relation.journal | Proceedings of the National Academy of Sciences | en_US |
dc.eprint.version | Final published version | en_US |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | en_US |
eprint.status | http://purl.org/eprint/status/PeerReviewed | en_US |
dspace.orderedauthors | Faber, Anthony C.; Farago, Anna F.; Costa, Carlotta; Dastur, Anahita; Gomez-Caraballo, Maria; Robbins, Rebecca; Wagner, Bethany L.; Rideout, William M.; Jakubik, Charles T.; Ham, Jungoh; Edelman, Elena J.; Ebi, Hiromichi; Yeo, Alan T.; Hata, Aaron N.; Song, Youngchul; Patel, Neha U.; March, Ryan J.; Tam, Ah Ting; Milano, Randy J.; Boisvert, Jessica L.; Hicks, Mark A.; Elmiligy, Sarah; Malstrom, Scott E.; Rivera, Miguel N.; Harada, Hisashi; Windle, Brad E.; Ramaswamy, Sridhar; Benes, Cyril H.; Jacks, Tyler; Engelman, Jeffrey A. | en_US |
dc.identifier.orcid | https://orcid.org/0000-0001-5785-8911 | |
mit.license | PUBLISHER_POLICY | en_US |
mit.metadata.status | Complete | |