Rapamycin rescues ABT-737 efficacy in small cell lung cancer
Eric E Gardner1, Nick Connis2, John T Poirier2
1Authors' Affiliations: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine; Departments of Oncology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New YorkAuthors' Affiliations: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine; Departments of Oncology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
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-1α-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 self-limiting 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.
Insights
Combining rapamycin with ABT-737 overcomes resistance in small cell lung cancer (SCLC) models. This combination therapy provides durable tumor regressions by modulating BAX protein levels, offering new hope for SCLC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Small cell lung cancer (SCLC) often overexpresses the antiapoptotic protein Bcl-2, leading to chemotherapy resistance.
- BH3 mimetic ABT-737 shows limited efficacy as a single agent in solid tumors, including SCLC, despite promise in hematologic malignancies.
Purpose of the Study:
- To investigate mechanisms of ABT-737 resistance in SCLC patient-derived xenograft (PDX) models.
- To evaluate combination therapies to overcome ABT-737 resistance and enhance anti-cancer efficacy in SCLC.
Main Methods:
- Utilized SCLC patient-derived xenograft (PDX) models to study ABT-737 resistance.
- Assessed the synergistic effects of combining ABT-737 with rapamycin (an mTOR inhibitor) or etoposide (a standard SCLC chemotherapeutic).
- Analyzed changes in HIF-1α-regulated transcripts and BAX/BAK protein levels.
Main Results:
- ABT-737 treatment led to short-lived responses associated with decreased HIF-1α-regulated transcripts.
- Combining rapamycin with ABT-737 demonstrated high synergy in vitro and induced durable tumor regressions in vivo without significant hematologic toxicity.
- ABT-737 monotherapy resulted in dose-dependent decreases in the proapoptotic protein BAX, while rapamycin increased BAX levels.
- Combination with etoposide did not yield tumor regressions.
Conclusions:
- The efficacy of single-agent ABT-737 in SCLC is limited by resistance mechanisms involving BAX downregulation.
- Combining rapamycin with ABT-737 enhances anti-cancer efficacy by maintaining or increasing BAX protein levels, overcoming resistance.
- These findings support the direct translational application of ABT-737 and rapamycin combination therapy in clinical trials for SCLC.
