Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer
Abstract
Small-cell lung cancer (SCLC) is an aggressive carcinoma with few effective treatment options beyond first-line chemotherapy. BH3 mimetics, such as ABT-263, promote apoptosis in SCLC cell lines, but early phase clinical trials demonstrated no significant clinical benefit. Here, we examine the sensitivity of a large panel of cancer cell lines, including SCLC, to ABT-263 and find that high Bcl2-interacting mediator of cell death (BIM) and low myeloid cell leukemia 1 (MCL-1) expression together predict sensitivity. SCLC cells relatively resistant to ABT-263 are sensitized by TORC1/2 inhibition via MCL-1 reduction. Combination of ABT-263 and TORC1/2 inhibition stabilizes or shrinks tumors in xenograft models, in autochthonous SCLC tumors in a genetically engineered mouse model, and in a patient-derived xenograft SCLC model. Collectively, these data support a compelling new therapeutic strategy for treating SCLC.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 03, 2015
- Source ID
- 10.1073/pnas.1411848112
Entities
People
- Aaron N Hata
- Ah Ting Tam
- Alan T. Yeo
- Anahita Dastur
- Anna F. Farago
- Anthony C. Faber
- Bethany L. Wagner
- Brad E. Windle
- Carlotta Costa
- Charles T. Jakubik
- Cyril H. Benes
- Elena J. Edelman
- Hiromichi Ebi
- Hisashi Harada
- Jeffrey A. Engelman
- Jessica L. Boisvert
- Jungoh Ham
- Maria Gomez-caraballo
- Mark A. Hicks
- Miguel N. Rivera
- Neha U. Patel
- Randy J. Milano
- Rebecca Robbins
- Ryan J. March
- Sarah Elmiligy
- Scott E. Malstrom
- Sridhar Ramaswamy
- Tyler Jacks
- William M. Rideout Iii
- Youngchul Song
Organizations
- American Cancer Society
- Burroughs Wellcome Fund
- Harvard Medical School
- Lung Cancer Research Foundation
- Massachusetts General Hospital
- Massachusetts Institute of Technology
- National Cancer Institute
- United States Department of Defense
- Uniting Against Lung Cancer
- Virginia Commonwealth University