Lipidomic Profiling of Lung Pleural Effusion Identifies Unique Metabotype for EGFR Mutants in Non-Small Cell Lung Cancer

Abstract

Cytology and histology forms the cornerstone for the diagnosis of non-small cell lung cancer (NSCLC) but obtaining sufficient tumour cells or tissue biopsies for these tests remains a challenge. We investigate the lipidome of lung pleural effusion (PE) for unique metabolic signatures to discriminate benign versus malignant PE and EGFR versus non-EGFR malignant subgroups to identify novel diagnostic markers that is independent of tumour cell availability. Using liquid chromatography mass spectrometry, we profiled the lipidomes of the PE of 30 benign and 41 malignant cases with or without EGFR mutation. Unsupervised principal component analysis revealed distinctive differences between the lipidomes of benign and malignant PE as well as between EGFR mutants and non-EGFR mutants. Docosapentaenoic acid and Docosahexaenoic acid gave superior sensitivity and specificity for detecting NSCLC when used singly. Additionally, several 20- and 22- carbon polyunsaturated fatty acids and phospholipid species were significantly elevated in the EGFR mutants compared to non-EGFR mutants. A 7-lipid panel showed great promise in the stratification of EGFR from non-EGFR malignant PE. Our data revealed novel lipid candidate markers in the non-cellular fraction of PE that holds potential to aid the diagnosis of benign, EGFR mutation positive and negative NSCLC.

Accurate Classification of Non-small Cell Lung Cancer (NSCLC) Pathology and Mapping of EGFR Mutation Spatial Distribution by Ambient Mass Spectrometry Imaging

“…These findings were consistent with the result that abnormal choline phospholipid metabolism is a hallmark of cancer (32). Two independent studies also revealed EGFR -mutated-positive NSCLC had a unique metabotype according to lipidomic profiling in lung pleural effusion (33) and phospholipids of tumor extracellular vesicles were different in gefitinib-resistant NSCLC cells from gefitinib-sensitive NSCLC cells (34). These results along with our observation showed phospholipids may represent reliable discriminative biomarkers associated with EGFR mutations status.…”

Prognostic factors of refractory NSCLC patients receiving anlotinib hydrochloride as the third- or further-line treatment

“…However, the impact of small molecule targeted therapy on the endocrine system and fat metabolism are less assessed, and the results are usually contradictory. For instance, Ho et al 16 have found that the levels of polyunsaturated fatty acids were elevated in patients with EGFR mutations, whereas reduced proportion of polyunsaturated fatty acids in the membrane phospholipids induced by inhibitors also lowered the activity of the EGFR membrane receptors, which shows a synergistic effect with gefitinib 17 . Other studies have also found that the mammalian target of sirolimus, which is a rapamycin (mTOR) inhibitor, increased the blood levels of total cholesterol and triglycerides 18,19 .…”

Reprogramming of Lipid Metabolism in Lung Cancer: An Overview with Focus on EGFR-Mutated Non-Small Cell Lung Cancer

“…In another study [57], it was shown that PUFAs with longer chain lengths, such as FA(20:5) and FA(22:6), were significantly higher in lung pleural effusions from EGFR mutant NSCLC patients compared to non-EGFR mutant, suggesting that they may play a role in sustaining the activation of mutant EGFR.…”