A study presented today at the IASLC World Conference on Lung Cancer 2022 in Vienna disclosed the clinical-relevant intertumoural heterogeneity of non-small cell lung cancer (NSCLC) driven by MET exon 14 skipping.
MET exon 14 skipping, as a rare driver for non-small cell lung cancer (NSCLC), can be successfully targeted by MET specific tyrosine kinase inhibitors (TKI) like savolitinib, tepotinib, and capmatinib.
Recent clinical trials of MET selective TKIs displayed encouraging clinical efficacy but nearly half of NSCLC patients with MET exon 14 skipping did not benefit from MET-TKI treatment, which indicated biological heterogeneity in NSCLCs driven by METex14 skipping.
To examine this further, Dr Yuchen Han, Shanghai Chest Hospital, China, aimed to disclose the intertumoural heterogeneity of METex14 skipping positive NSCLCs at the functional level.
To accomplish this, Dr. Han and her colleagues examined 126 formalin fixed, paraffin embedded specimens from NSCLC patients with METex14 skipping from the Department of Pathology at Shanghai Chest Hospital from April 2017 to December 2020.
All samples were subjected to targeted RNA sequencing using a panel consisting of 2660 onco-immunology genes.
Functional enrichment of each sample was evaluated by single sample Gene Set Enrichment Analysis (ssGSEA) and pathway-level unsupervised clustering was conducted to identify molecular subtypes in METex14 skipping positive patients.
Subtype-specific pathways, tumour microenvironment, and clinic-pathological features were further analysed.
Four molecular subtypes were established, including subtype A (33.3%), subtype B (15.1%), subtype C (14.3%), and subtype D (37.3%).
“This study disclosed the clinical-relevant intertumoural heterogeneity of NSCLCs driven by MET exon 14 skipping. Based on the molecular subtyping, subtype A was more sensitive to MET-TKIs, while subtype D was putatively resistant to MET-TKIs,” said Dr Han. “Of note, subtype C might be more vulnerable to immunotherapy.”
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