Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Mol Cancer Ther. 2016 Jun;15(6):1248-60. doi: 10.1158/1535-7163.MCT-15-0885. Epub 2016 Mar 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Biphenyl Compounds / administration & dosage*
  • Biphenyl Compounds / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Synergism
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Mice
  • Nitrophenols / administration & dosage*
  • Nitrophenols / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Piperazines / administration & dosage
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction / drug effects
  • Small Cell Lung Carcinoma / drug therapy*
  • Small Cell Lung Carcinoma / metabolism
  • Sulfonamides / administration & dosage*
  • Sulfonamides / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • ABT-737
  • Antineoplastic Agents
  • Biphenyl Compounds
  • Nitrophenols
  • Piperazines
  • Protein Kinase Inhibitors
  • Sulfonamides
  • BMX protein, human
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases