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Published on: March 6, 2018
PLXNA1 confers enzalutamide resistance in prostate cancer via AKT signaling pathway
Jing Hu1, Jing Zhang2, Bo Han3
1Department of Pathology, Qilu Hospital, Shandong University, Jinan 250012, China; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Abstract:
Although targeting the androgen signaling pathway by androgen receptor (AR) inhibitors, including enzalutamide, has shown therapeutic effectiveness, inevitable emergence of acquired resistance remains a critical challenge in the treatment of advanced prostate cancer (PCa). Recognizing targetable genomic aberrations that trigger endocrine treatment failure holds great promise for advancing therapeutic interventions. Here, we characterized PLXNA1, amplified in a subset of PCa patients, as a contributor to enzalutamide resistance (ENZR). Elevated PLXNA1 expression facilitated PCa proliferation under enzalutamide treatment due to AKT signaling activation. Mechanistically, PLXNA1 recruited NRP1 forming a PLXNA1-NRP1 complex, which in turn potentiated the phosphorylation of the AKT. Either inhibiting PLXNA1-NRP1 complex with an NRP1 inhibitor, EG01377, or targeting PLXNA1-mediated ENZR with AKT inhibitors, abolished the pro-resistance phenotype of PLXNA1. Taken together, combination of AKT inhibitor and AR inhibitors presents a promising therapeutic strategy for PCa, especially in advanced PCa patients exhibiting PLXNA1 overexpression.
Insights
Acquired resistance to androgen receptor (AR) inhibitors like enzalutamide is a major challenge in advanced prostate cancer (PCa). PLXNA1 amplification drives this resistance by activating AKT signaling, suggesting combination therapy with AKT inhibitors may overcome treatment failure.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Androgen receptor (AR) inhibitors, such as enzalutamide, are effective against advanced prostate cancer (PCa).
- Acquired resistance to these therapies is a significant clinical challenge.
- Identifying genomic alterations driving treatment failure is crucial for developing new strategies.
Purpose of the Study:
- To investigate the role of PLXNA1, amplified in a subset of PCa patients, in acquired resistance to enzalutamide.
- To elucidate the molecular mechanisms by which PLXNA1 contributes to enzalutamide resistance (ENZR).
Main Methods:
- Characterization of PLXNA1 amplification and expression in PCa.
- Investigating the effect of elevated PLXNA1 on PCa cell proliferation under enzalutamide treatment.
- Analyzing the interaction between PLXNA1 and NRP1 and its impact on AKT signaling.
- Evaluating the efficacy of inhibiting the PLXNA1-NRP1 complex or targeting AKT signaling.
Main Results:
- PLXNA1 amplification was identified in a subset of PCa patients.
- Elevated PLXNA1 expression promoted PCa proliferation during enzalutamide treatment by activating AKT signaling.
- PLXNA1 formed a complex with NRP1, enhancing AKT phosphorylation.
- Inhibition of the PLXNA1-NRP1 complex or AKT signaling reversed the pro-resistance phenotype.
Conclusions:
- PLXNA1 is a key driver of enzalutamide resistance in PCa.
- The PLXNA1-NRP1 complex activates AKT signaling, contributing to treatment failure.
- Combination therapy with AKT inhibitors and AR inhibitors shows promise for treating advanced PCa with PLXNA1 overexpression.
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