Strategies to Overcome Resistance to Osimertinib in EGFR-Mutated Lung Cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Non-small-cell lung cancer (NSCLC) is the most common lung malignancy.
• Activating mutations in the epidermal growth factor receptor (EGFR) are common in NSCLC patients.
• Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), has significantly improved outcomes for patients with EGFR-mutated NSCLC.

Purpose of the Study:

• To review current strategies for overcoming osimertinib resistance in EGFR-mutated NSCLC.
• To highlight emerging therapeutic approaches being investigated in preclinical and clinical settings.

Main Methods:

• Literature review of preclinical and clinical studies on osimertinib resistance mechanisms.
• Focus on novel therapeutic strategies including fourth-generation TKIs, PROTACs, bispecific antibodies, and antibody-drug conjugates (ADCs).

Main Results:

• Resistance to osimertinib is inevitable and can occur through on-target (e.g., EGFR C797S mutation) or off-target mechanisms (e.g., MET amplification, EMT).
• Emerging strategies aim to target these resistance mechanisms effectively.
• Combination therapies are being explored to enhance treatment efficacy.

Conclusions:

• Overcoming osimertinib resistance requires a multifaceted approach.
• Novel therapeutic agents and combination strategies hold promise for improving long-term outcomes in EGFR-mutated NSCLC patients.
• Continued research into resistance mechanisms and novel treatments is essential.