Abstract 4676: Overcoming EGFR-induced resistance to enzalutamide in castration-resistant prostate cancer
Authors: Steele Thomas M. , Jathal Maitreyee K. , Siddiqui Salma , Ghosh Paramita M. 
Published: July 2016

Background: The androgen receptor (AR) remains a major therapeutic target in patients with castration-resistant prostate cancer (CRPC). Enzalutamide, an AR inhibitor that is FDA-approved for patients with CRPC, prevents ligand induced AR transcriptional activity, but some initial responders eventually become resistant to the drug. The expression and activity of the EGFR/ErbB family of receptor tyrosine kinases also increases in CRPC patients. The present work was undertaken to determine whether the activation of EGFR family (EGFR/ErbB2/ErbB3/ErbB4) may be responsible for enzalutamide resistance and whether treatment with receptor tyrosine kinase inhibitors would overcome this effect.

Methods: Human-patient-derived androgen-dependent and CRPC prostate tumor cells were grown in 10% Fetal Bovine Serum (FBS). Protein expression and phosphorylation status of the EGFR family were determined by immunoblotting techniques. MTT assays were used to determine the viability of cells treated with enzalutamide, lapatinib (HER2/EGFR inhibitor), erlotinib (EGFR inhibitor), or dacomitinib (pan-ErbB inhibitor). A Luciferase Assay kit (Roche) was used to determine AR transcriptional activity. Lapatinib was obtained from LC Laboratories while erlotinib and dacomitinib were obtained from Selleck Chemicals. Enzalutamide was kindly provided by Medivation Inc.

Results: In viability assays, erlotinib and dacomitinib were more effective than lapatinib in sensitizing CRPC cells to enzalutamide. Enzalutamide suppressed AR transcriptional activity, either alone or in combination with lapatinib, erlotinib, or dacomitinib. Erlotinib, lapatinib, and dacomitinib equally inhibited EGFR and ErbB3 phosphorylation. However, in EGF stimulated cells, erlotinib and dacomitinib—but not lapatinib—suppressed ERK 1/2 phosphorylation at Tyr202/Thr204, indicating a stark difference in downstream inhibition and potentially proliferation.

Conclusions: The above results indicate that ERK 1/2 may play an important role in reducing the efficacy of enzalutamide by itself and in combination with lapatinib. Furthermore, lapatinib's inability to prevent ERK phosphorylation upon EGF stimulation may play a role in its ineffectiveness in prostate cancer. Our preliminary preclinical data indicate that co-administration of enzalutamide with an EGFR targeted inhibitor may be a suitable therapeutic approach towards overcoming enzalutamide resistance in vitro. We are testing whether ERK 1/2 or MEK may be effective in reducing this ERK specific enzalutamide resistance. These strategies may potentially prolong enzalutamide sensitivity in CRPC patients.

Citation Format: Thomas M. Steele, Maitreyee K. Jathal, Salma Siddiqui, Paramita M. Ghosh. Overcoming EGFR-induced resistance to enzalutamide in castration-resistant prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4676.