Rapamycin rescues ABT-737 efficacy in small cell lung cancer Journal Article


Authors: Gardner, E. E.; Connis, N.; Poirier, J. T.; Cope, L.; Dobromilskaya, I.; Gallia, G. L.; Rudin, C. M.; Hann, C. L.
Article Title: Rapamycin rescues ABT-737 efficacy in small cell lung cancer
Abstract: Overexpression of the antiapoptotic protein Bcl-2 is observed in the majority of small cell lung cancer (SCLC) cases and is associated with resistance to chemotherapy. While targeting Bcl-2 in hematologic malignancies continues to show signs of promise, translating the BH3 mimetic ABT-737 (or ABT-263; navitoclax) to the clinic for solid tumors has remained problematic, with limited single-Agent activity in early-phase clinical trials. Here, we used patient-derived xenograft (PDX) models of SCLC to study ABT-737 resistance and demonstrated that responses to ABT-737 are short lived and coincide with decreases in HIF-1a-regulated transcripts. Combining the mTOR inhibitor rapamycin with ABT-737 rescued this resistance mechanism, was highly synergistic in vitro, and provided durable tumor regressions in vivo without notable hematologic suppression. In comparison, tumor regressions did not occur when ABT-737 was combined with etoposide, a gold-standard cytotoxic for SCLC therapy. Rapamycin exposure was consistently associated with an increase in the proapoptotic protein BAX, whereas ABT-737 caused dose-dependent decreases in BAX. As ABT-737 triggers programmed cell death in a BAX/BAK-dependent manner, we provide preclinical evidence that the efficacy of ABT-737 as a single agent is selflimiting in SCLC, but the addition of rapamycin can maintain or increase levels of BAX protein and markedly enhance the anticancer efficacy of ABT-737. These data have direct translational implications for SCLC clinical trials. © 2014 American Association for Cancer Research.
Keywords: immunohistochemistry; controlled study; drug efficacy; drug potentiation; nonhuman; mouse; animal tissue; protein bcl 2; apoptosis; etoposide; animal model; in vivo study; antineoplastic activity; in vitro study; tumor regression; tumor xenograft; lung small cell cancer; hypoxia inducible factor 1alpha; rapamycin; 4 [4 (4' chloro 2 biphenylylmethyl) 1 piperazinyl] n [4 [3 dimethylamino 1 (phenylthiomethyl)propylamino] 3 nitrobenzenesulfonyl]benzamide; protein bax; protein bak; navitoclax; human; female; priority journal; article; cancer cell line
Journal Title: Cancer Research
Volume: 74
Issue: 10
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2014-05-15
Start Page: 2846
End Page: 2856
Language: English
DOI: 10.1158/0008-5472.can-13-3460
PROVIDER: scopus
PUBMED: 24614082
PMCID: PMC4510983
DOI/URL:
Notes: Cancer Res. -- Export Date: 8 July 2014 -- CODEN: CNREA -- Source: Scopus
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  1. Charles Rudin
    489 Rudin
  2. John Thomas Poirier
    82 Poirier
  3. Eric Edison Gardner
    14 Gardner