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Targeting WEE1 to Overcome ARID1A Mutation-Driven Osimertinib Resistance in EGFR-Mutant Lung Cancer
Koji Fukuda1, Shigeki Nanjo2, Shinji Takeuchi3
1Division of Innovative Cancer Control Research, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.
Introduction:
Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), is commonly used as a first-line treatment for EGFR-mutant NSCLC. Nevertheless, despite its efficacy, resistance remains a major clinical challenge with unknown underlying mechanisms. This study aimed to investigate the mechanisms driving osimertinib resistance and identify therapeutic strategies.
Methods:
Using a mouse model of leptomeningeal carcinomatosis, we induced osimertinib resistance and performed next-generation sequencing to characterize resistance-associated mutations. We also analyzed clinical samples to correlate ARID1A status with progression-free survival and overall survival in patients receiving osimertinib.
Results:
Mutations in the AT-rich interacting domain-containing protein 1A (ARID1A) gene were the most prevalent in resistant cells. Functional assays revealed that ARID1A knockout in parental cells and wild-type ARID1A gene expression in resistant cells were critical in conferring osimertinib resistance. A Clustered Regularly Interspaced Short Palindromic Repeats-Cas9 knockout screen identified WEE1 kinase as a potent enhancer of apoptosis in ARID1A-mutant osimertinib-resistant cells. Mechanistically, ARID1A-mutant cells exhibited reduced expression of genes involved in cell cycle regulation and DNA repair, rendering them particularly sensitive to WEE1 inhibition. In the leptomeningeal carcinomatosis mouse model, the combined inhibition of EGFR and WEE1 significantly suppressed tumor growth. Clinically, patients with ARID1A mutations treated with osimertinib had significantly shorter median progression-free survival (6.25 versus 18.0 months, p = 0.0036) and overall survival (17.0 versus 34.0 months, p = 0.024) than did those with wild-type ARID1A.
Conclusions:
These findings suggest that ARID1A mutations are critical biomarkers for osimertinib resistance and highlight WEE1 inhibition as a promising therapeutic approach for ARID1A-mutant osimertinib-resistant NSCLC.
Insights
AT-rich interacting domain-containing protein 1A (ARID1A) mutations drive osimertinib resistance in EGFR-mutant NSCLC. WEE1 kinase inhibition offers a promising therapeutic strategy for patients with ARID1A mutations, improving outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Osimertinib is a first-line EGFR tyrosine kinase inhibitor (EGFR-TKI) for EGFR-mutant NSCLC.
- Resistance to osimertinib is a significant clinical challenge with incompletely understood mechanisms.
- Identifying resistance drivers and therapeutic strategies is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the mechanisms underlying osimertinib resistance in EGFR-mutant NSCLC.
- To identify potential therapeutic targets for overcoming osimertinib resistance.
- To evaluate the clinical significance of ARID1A mutations in osimertinib-treated patients.
Main Methods:
- Osimertinib resistance was induced in a mouse model of leptomeningeal carcinomatosis.
- Next-generation sequencing and CRISPR-Cas9 knockout screens were employed to identify resistance mutations and therapeutic targets.
- Clinical samples were analyzed to correlate ARID1A status with patient survival outcomes.
Main Results:
- Mutations in the AT-rich interacting domain-containing protein 1A (ARID1A) gene were identified as a primary mechanism of osimertinib resistance.
- ARID1A mutations confer resistance by altering cell cycle regulation and DNA repair pathways.
- WEE1 kinase inhibition demonstrated efficacy in overcoming ARID1A-mutant osimertinib resistance, both in preclinical models and in combination with EGFR inhibition.
- Clinically, ARID1A mutations were associated with significantly shorter progression-free and overall survival in patients treated with osimertinib.
Conclusions:
- ARID1A mutations serve as critical biomarkers for predicting osimertinib resistance in NSCLC.
- Targeting WEE1 kinase represents a promising therapeutic strategy for ARID1A-mutant osimertinib-resistant NSCLC.
- Combined inhibition of EGFR and WEE1 warrants further clinical investigation for this patient population.
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