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-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.
authors.affiliation: Authors' 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.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Gardner
authors.affiliation: Authors' 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.
authors.forename: Nick
authors.initials: N
authors.lastname: Connis
authors.affiliation: Authors' 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.
authors.forename: John T
authors.initials: JT
authors.lastname: Poirier
authors.affiliation: Authors' 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.
authors.forename: Leslie
authors.initials: L
authors.lastname: Cope
authors.affiliation: Authors' 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.
authors.forename: Irina
authors.initials: I
authors.lastname: Dobromilskaya
authors.affiliation: Authors' 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.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Gallia
authors.affiliation: Authors' 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 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.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.affiliation: Authors' 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 chann1@jhmi.edu.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Hann
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009596:Nitrophenols / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011897:Random Allocation; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D005047:Etoposide; D020123:Sirolimus