title: Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC.
abstract: Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell-derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient-derived model in vivo These data add to a body of evidence that this combination should move toward the clinic. Mol Cancer Ther; 15(6); 1248-60. ©2016 AACR.
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom.
authors.forename: Danielle S
authors.initials: DS
authors.lastname: Potter
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom.
authors.forename: Melanie
authors.initials: M
authors.lastname: Galvin
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom.
authors.forename: Stewart
authors.initials: S
authors.lastname: Brown
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom.
authors.forename: Alice
authors.initials: A
authors.lastname: Lallo
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom.
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Hodgkinson
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom. Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Fiona
authors.initials: F
authors.lastname: Blackhall
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Morrow
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom. CRUK Lung Cancer Centre of Excellence, Manchester, United Kingdom. caroline.dive@cruk.manchester.ac.uk.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D009596:Nitrophenols / Q000008:administration & dosage* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; 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; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C492367:BMX protein, human; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases