MERTK activation drives osimertinib resistance in EGFR-mutant non-small cell lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Acquired resistance to osimertinib (OSI) is a significant challenge in treating EGFR-mutated non-small cell lung cancer (NSCLC).
• Mechanisms underlying OSI resistance are not fully understood, hindering the development of effective therapeutic strategies.

Purpose of the Study:

• To investigate the role of MERTK signaling in acquired resistance to osimertinib in NSCLC.
• To evaluate the efficacy of a MERTK kinase inhibitor, MRX-2843, in combination with OSI to overcome resistance.

Main Methods:

• Utilized EGFR-mutated NSCLC cell lines and xenograft models.
• Assessed downstream signaling pathways (PI3K/AKT, MAPK/ERK) in response to GAS6, EGF, OSI, and MRX-2843.
• Quantified MERTK and ligand expression in tumors before and after OSI treatment.
• Evaluated tumor growth suppression in vivo using combination therapy.

Main Results:

• GAS6, a MERTK ligand, activated oncogenic signaling in OSI-resistant NSCLC cells.
• MRX-2843 resensitized NSCLC cells to OSI and demonstrated greater efficacy in OSI-resistant cells, suggesting acquired MERTK dependence.
• MERTK and its ligands were upregulated in EGFR-mutated tumors post-OSI treatment.
• Combination therapy with MRX-2843 and OSI achieved durable tumor growth suppression in vivo.

Conclusions:

• MERTK activation is a key mechanism driving bypass signaling in both treatment-naive and OSI-resistant EGFR-mutated NSCLC.
• Combination therapy with MRX-2843 and OSI shows promise for overcoming osimertinib resistance and improving clinical outcomes in NSCLC patients.