Lung adenocarcinoma surfaceome remodeling with EGFR inhibitors uncovers placental alkaline phosphatase as a target
Yihui Chen1, Rongzhang Dou1, Monica J Hong1
1Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
Treatment of lung adenocarcinomas (LUADs) that exhibit activated epidermal growth factor receptor (EGFR) with EGFR tyrosine kinase inhibitors (TKIs) has limited efficacy. Assessment of the impact of EGFR TKI on the LUAD surfaceome remodeling reveals potential therapeutic targets. We identify placental type alkaline phosphatase (ALPP), which has restricted expression in normal tissues, among upregulated surface proteins following EGFR TKI treatment of both TKI sensitive as well as resistant cells. EGF treatment represses ALPP expression, whereas EGFR TKIs upregulate its expression through dephosphorylation and activation of FoxO3a, a transcriptional regulator that binds to the promoter region of ALPP. The combination of EGFR TKI plus ALPP antibody conjugated with monomethyl auristatin F enhances tumor killing in osimertinib-sensitive and -resistant LUAD models compared to either treatment alone. Our findings support a combination therapy involving an EGFR inhibitor together with an ALPP antibody drug conjugate for EGFR-mutated LUADs.
Insights
EGFR inhibitors show limited efficacy for lung cancer. Upregulation of ALPP surface protein after treatment suggests a new therapeutic target. Combining EGFR inhibitors with ALPP antibodies improves tumor killing.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have limited efficacy in treating lung adenocarcinomas (LUADs) with activated EGFR.
- Understanding the impact of EGFR TKI on the LUAD surfaceome is crucial for identifying novel therapeutic targets.
Purpose of the Study:
- To identify and characterize novel surface proteins upregulated by EGFR TKI treatment in LUAD cells.
- To investigate the mechanism of ALPP regulation by EGFR signaling and its potential as a therapeutic target.
Main Methods:
- Analysis of LUAD surfaceome remodeling following EGFR TKI treatment.
- Investigating the role of FoxO3a in regulating ALPP expression.
- Evaluating the efficacy of combination therapy using EGFR TKI and an ALPP antibody-drug conjugate in LUAD models.
Main Results:
- Placental type alkaline phosphatase (ALPP) was identified as a significantly upregulated surface protein in both TKI-sensitive and TKI-resistant LUAD cells after EGFR TKI treatment.
- EGFR TKIs upregulate ALPP expression by activating the transcriptional regulator FoxO3a, while EGF treatment represses ALPP.
- Combination therapy with EGFR TKI and an ALPP antibody conjugated with monomethyl auristatin F demonstrated enhanced tumor killing in both osimertinib-sensitive and -resistant LUAD models.
Conclusions:
- ALPP is a promising therapeutic target in EGFR-mutated LUADs, particularly in cases with limited response to EGFR TKIs.
- Combination therapy involving EGFR inhibitors and ALPP antibody-drug conjugates offers a potential strategy to overcome TKI resistance and improve treatment outcomes in LUAD.
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