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-XL inhibition represents a valuable therapeutic strategy.
Implications: 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.
Overview: Synthetic lethality in PTEN-mutant prostate cancer cells with combined PI3K/Akt and BCL-XL inhibition. PTEN-mutant prostate cancer cells expressing ITGA5 bind to fibronectin in the putative bone marrow niche and transduce survival signals to BCL-XL. Additional 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://ift.tt/2gGdwX0. Mol Cancer Res; 14(12); 1176–81. ©2016 AACR.
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