MET Exon 14-altered Lung Cancers and MET Inhibitor Resistance

Area of Science:

• Oncology
• Molecular Biology
• Genomics and Proteomics

Background:

• MET tyrosine kinase inhibitors (TKIs) demonstrate modest clinical efficacy in MET exon 14-altered lung cancers.
• Primary resistance mechanisms to MET TKIs in these cancers are not well understood.
• Comprehensive proteomic analyses have not been previously conducted in this context.

Purpose of the Study:

• To investigate the mechanisms of primary resistance to MET TKIs in MET exon 14-altered lung cancers.
• To perform comprehensive proteomic and genomic analyses to identify factors associated with TKI response.
• To evaluate the association between genomic alterations, MET protein expression, and clinical outcomes (ORR, PFS).

Main Methods:

• Hybrid capture-based DNA sequencing, targeted RNA sequencing, and cell-free DNA sequencing were performed.
• Selected reaction monitoring mass spectrometry (SRM-MS) and immunohistochemistry were used to assess MET protein expression.
• Associations between genomic factors, MET expression, overall response rate (ORR), and progression-free survival (PFS) were analyzed.

Main Results:

• Genomic factors, including novel and known alterations, were not associated with ORR or PFS in MET TKI-treated patients.
• MET protein expression, detected by SRM-MS and immunohistochemistry, was significantly associated with TKI benefit.
• Patients with MET H-score ≥ 200 exhibited longer PFS (10.4 months) compared to those below the cutoff (5.5 months).

Conclusions:

• Genomic analyses did not reveal a mechanism for primary resistance to MET TKIs in MET exon 14-altered lung cancers.
• MET protein expression is a key determinant of response to MET TKI therapy in this patient population.
• Future trials should consider interrogating the proteome alongside the genome to guide TKI treatment strategies.