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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