Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Molecularly targeted therapies, like EGFR inhibitors, have improved lung cancer outcomes.
• However, incomplete treatment responses and limited long-term survival persist due to co-occurring genetic alterations.
• The role of genetic alterations co-occurring with mutant EGFR remains largely unexplored.

Purpose of the Study:

• To investigate the functional impact of RNA-binding motif 10 (RBM10) inactivation in EGFR-mutant lung cancer.
• To determine if RBM10 deficiency affects sensitivity to EGFR inhibitors.
• To explore the therapeutic implications of RBM10's role in apoptosis regulation.

Main Methods:

• Utilized patient-derived EGFR-mutant tumor models.
• Assessed the effect of RBM10 deficiency on EGFR inhibitor efficacy.
• Analyzed mRNA alternative splicing of Bcl-x and its isoforms (Bcl-xS and Bcl-xL).
• Correlated RBM10 deficiency with clinical response to EGFR inhibitors.

Main Results:

• RBM10 deficiency significantly decreased EGFR inhibitor efficacy in preclinical models.
• RBM10 deficiency altered Bcl-x splicing, reducing the proapoptotic Bcl-xS/antiapoptotic Bcl-xL ratio.
• RBM10 inactivation diminished EGFR inhibitor-induced apoptosis.
• RBM10 deficiency served as a biomarker for poor response to EGFR inhibitors in patients.

Conclusions:

• RBM10 inactivation contributes to resistance against EGFR inhibitors in lung cancer.
• RBM10 regulates apoptosis sensitivity through alternative splicing of Bcl-x.
• Combined inhibition of Bcl-xL and mutant EGFR can overcome RBM10-deficiency-induced resistance.
• Co-occurring genetic alterations, like RBM10 deficiency, significantly impact targeted therapy efficacy.