title: Synthetic Lethality in PTEN-Mutant Prostate Cancer Is Induced by Combinatorial PI3K/Akt and BCL-XL Inhibition.
abstract: The bone-conserved metastatic phenotype of prostate cancer is a prototype of nonrandom metastatic behavior. Adhesion of prostate cancer cells to fibronectin via the integrin α5 (ITGA5) has been proposed as a candidate bone marrow niche localization mechanism. We hypothesized that the mechanisms whereby ITGA5 regulates the adhesion-mediated survival of prostate cancer cells will define novel therapeutic approaches. ITGA5 shRNA reduced expression of BCL-2 family members and induced apoptosis in PC-3 cells. In these PTEN-mutant cells, pharmacologic inhibition of the PI3K signaling pathway in combination with ITGA5 knockdown enhanced apoptosis. Chemical parsing studies with BH3 mimetics indicated that PI3K/Akt inhibition in combination with BCL-XL-specific inhibition induces synergistic apoptosis specifically in PTEN-mutant prostate cancer cells, whereas single-agent PI3K/Akt inhibitors did not. Given the importance of PTEN loss in the progression of prostate and other cancers, synthetic lethality induced by combinatorial PI3K/Akt and BCL-XLinhibition represents a valuable therapeutic strategy.
  
  
  
  Activation of the PI3K pathway through PTEN loss represents a major molecular pathway in the progression of prostate and other cancers. This study defines a synthetic lethal therapeutic combination with significant translational potential.
  
  
  
  Synthetic lethality in PTEN-mutant prostate cancer cells with combined PI3K/Akt and BCL-XLinhibition. PTEN-mutant prostate cancer cells expressing ITGA5 bind to fibronectin in the putative bone marrow niche and transduce survival signals to BCL-XLAdditional PTEN-regulated signals independent of the PI3K/Akt pathway likely feed into the BCL-XL-regulated survival program to explain synthetic lethality observed with the combination.Visual Overview: http://mcr.aacrjournals.org/content/early/2016/12/02/1541-7786.MCR-16-0202/F1.large.jpg. Mol Cancer Res; 14(12); 1176-81. ©2016 AACR.
authors: Molecular Oncology Research Institute, Department of Hematology-Oncology, Tufts Medical Center, Boston, Massachusetts.
authors: Wenying
authors: W
authors: Ren
authors: Molecular Oncology Research Institute, Department of Hematology-Oncology, Tufts Medical Center, Boston, Massachusetts.
authors: Raghav
authors: R
authors: Joshi
authors: Molecular Oncology Research Institute, Department of Hematology-Oncology, Tufts Medical Center, Boston, Massachusetts. pmathew@tuftsmedicalcenter.org.
authors: Paul
authors: P
authors: Mathew
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004359:Drug Therapy, Combination; D006801:Humans; D039482:Integrin alpha5 / Q000235:genetics*; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D000072020:Synthetic Lethal Mutations; D051020:bcl-X Protein / Q000037:antagonists & inhibitors
chemical_list: D000631:Aminopyridines; D000814:Aniline Compounds; C494811:BCL2L1 protein, human; D039482:Integrin alpha5; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D013449:Sulfonamides; D051020:bcl-X Protein; C583616:ipatasertib; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C528561:navitoclax