A destabilizing Y891D mutation in activated EGFR impairs sensitivity to kinase inhibition

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard treatments for EGFR-mutated non-small cell lung carcinoma (NSCLC).
• Therapeutic resistance to EGFR TKIs, often driven by secondary EGFR mutations, remains a significant clinical obstacle.

Purpose of the Study:

• To investigate a novel de novo EGFR Y891D secondary alteration in NSCLC with an existing EGFR L858R mutation.
• To elucidate the mechanism by which EGFR Y891D contributes to TKI resistance.

Main Methods:

• Identification of EGFR Y891D mutation in a NSCLC patient sample with EGFR L858R.
• Functional studies using Ba/F3 cell lines to assess TKI sensitivity of EGFR L858R + Y891D mutations.
• Analysis of ATP affinity and steric hindrance associated with the Y891D mutation.

Main Results:

• The EGFR L858R + Y891D double mutation confers reduced sensitivity to first and second-generation EGFR TKIs.
• The Y891D mutation does not significantly alter EGFR's ATP binding affinity or cause steric hindrance to TKI binding.
• EGFR Y891D appears to destabilize the EGFR L858R mutation, potentially leading to protein misfolding.

Conclusions:

• EGFR Y891D may confer TKI resistance through a mechanism involving protein destabilization and misfolding, rather than altered ATP affinity or steric hindrance.
• This finding suggests protein misfolding as a potential resistance mechanism to EGFR inhibitors in NSCLC.
• Further research into protein misfolding could reveal new therapeutic strategies for overcoming TKI resistance.