Abstract
Docetaxel remains the standard-of-care for men diagnosed with metastatic castrate-resistant prostate cancer (CRPC). However, only approximately 50% of patients benefit from treatment and all develop docetaxel-resistant disease. Here, we characterize global perturbations in tyrosine kinase signaling associated with docetaxel resistance and thereby develop a potential therapeutic strategy to reverse this phenotype. Using quantitative mass spectrometry-based phosphoproteomics, we identified that metastatic docetaxel-resistant prostate cancer cell lines (DU145-Rx and PC3-Rx) exhibit increased phosphorylation of focal adhesion kinase (FAK) on Y397 and Y576, in comparison with parental controls (DU145 and PC3, respectively). Bioinformatic analyses identified perturbations in pathways regulating focal adhesions and the actin cytoskeleton and in protein-protein interaction networks related to these pathways in docetaxel-resistant cells. Treatment with the FAK tyrosine kinase inhibitor (TKI) PF-00562271 reduced FAK phosphorylation in the resistant cells, but did not affect cell viability or Akt phosphorylation. Docetaxel administration reduced FAK and Akt phosphorylation, whereas cotreatment with PF-00562271 and docetaxel resulted in an additive attenuation of FAK and Akt phosphorylation and overcame the chemoresistant phenotype. The enhanced efficacy of cotreatment was due to increased autophagic cell death, rather than apoptosis. These data strongly support that enhanced FAK activation mediates chemoresistance in CRPC, and identify a potential clinical niche for FAK TKIs, where coadministration with docetaxel may be used in patients with CRPC to overcome chemoresistance.
Highlights
Prostate cancer remains the third leading cause of cancer-related death in men in the developed world [1] with castrate-resistant prostate cancer (CRPC) being the lethal stage of the disease
Studies in ovarian cancer cell lines and xenografts demonstrated that knockdown of focal adhesion kinase (FAK) expression enhanced docetaxel efficacy in docetaxelsensitive and docetaxel-resistant models in vitro and in vivo [31, 32]
PF00562271 is a potent inhibitor of CYP3A, whereas PF04554878 is a weak CYP3A inhibitor with a low potential for CYP3A drug–drug interaction [35, 36], making this second-generation compound the preferred FAK inhibitor for development in combination with cytotoxics
Summary
Prostate cancer remains the third leading cause of cancer-related death in men in the developed world [1] with castrate-resistant prostate cancer (CRPC) being the lethal stage of the disease. Docetaxel only clinically benefits approximately 50% of men at the cost of significant toxicity [2] Those patients who respond develop resistance to chemotherapy. Accumulating evidence has implicated several mechanisms in the development of docetaxel resistance These include increased drug efflux through enhanced expression of multidrug resistance proteins (MDRP; 4) and perturbations in intra- and intercellular signaling pathways. FAK and Docetaxel Resistance docetaxel-therapy benefited from cabazitaxel treatment with an improvement in median overall survival of approximately 3 months [17]. Such limited success by conventional candidate-based approaches in the clinical setting highlights an urgent need to better understand the underlying molecular mechanism of chemoresistance and design novel therapeutic strategies. Our findings provide important insights into the biology of chemoresistance in prostate cancer and have significant implications for the development of therapeutic strategies
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