Potential Utility of a 4th-Generation EGFR-TKI and Exploration of Resistance Mechanisms-An In Vitro Study

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Acquired resistance to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) is a significant clinical challenge in lung cancer treatment.
• Secondary mutations, such as T790M and C797S, are key drivers of resistance to first/second-generation (1/2G) and third-generation (3G) EGFR-TKIs, respectively.
• Novel fourth-generation (4G) EGFR-TKIs are being developed to overcome resistance, including mutations like C797S.

Purpose of the Study:

• To evaluate the efficacy of a novel 4G EGFR-TKI (BI4020) in lung cancer models with EGFR mutations, particularly after resistance to front-line osimertinib.
• To investigate the resistance mechanisms against the 4G EGFR-TKI BI4020.

Main Methods:

• Utilized Ba/F3 cell models engineered to mimic resistant tumors following osimertinib failure due to secondary mutations.
• Compared the efficacy of seven TKIs, including BI4020, against these resistant cell models.
• Established acquired resistance to BI4020 through chronic drug exposure and analyzed resistance mechanisms, including secondary EGFR mutations and off-target alterations.

Main Results:

• Ba/F3 cells with osimertinib-resistant secondary mutations were unresponsive to all tested 3G TKIs.
• BI4020 demonstrated activity against C797S-positive cells but was ineffective against L718Q-positive cells; erlotinib showed activity against all tested Ba/F3 cells.
• BI4020-resistant cells exhibited MET gene amplification (sensitive to capmatinib + BI4020) or epithelial-to-mesenchymal transition, without secondary EGFR mutations.

Conclusions:

• Erlotinib may be a more suitable option than 4G TKIs for overcoming secondary mutations after front-line osimertinib treatment.
• Off-target resistance mechanisms that confer resistance to earlier-generation TKIs also lead to resistance against 4G TKIs.