Portal de Periódicos da CAPES

Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer

2015; National Academy of Sciences; Volume: 112; Issue: 11 Linguagem: Inglês

10.1073/pnas.1411848112

1091-6490

Anthony C. Faber, Anna F. Farago, Carlotta Costa, Anahita Dastur, María Gomez‐Caraballo, Rebecca Robbins, Bethany L. Wagner, William M. Rideout, Charles T. Jakubik, Jungoh Ham, Elena J. Edelman, Hiromichi Ebi, Alan T. Yeo, Aaron N. Hata, Youngchul Song, Neha U. Patel, Ryan J. March, Ah Ting Tam, Randy Milano, Jessica L. Boisvert, Mark Hicks, Sarah Elmiligy, Scott Malstrom, Miguel N. Rivera, Hisashi Harada, Brad E. Windle, Sridhar Ramaswamy, Cyril H. Benes, Tyler Jacks, Jeffrey A. Engelman,

Peptidase Inhibition and Analysis

Significance 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.