Abstract
The oral multi-targeted tyrosine kinase inhibitor (TKI) anlotinib is effective for non-small cell lung cancer (NSCLC) in clinical trials at 3rd line. However, a fraction of patients remains non-responsive, raising the need of how to identify anlotinib-responsive patients. In the present study, we aimed to screen potential biomarkers for anlotinib-responsive stratification via integrated transcriptome analysis. Comparing with the anlotinib-sensitive lung cancer cell NCI-H1975, we found 1,315 genes were differentially expressed in anlotinib-resistant NCI-H1975 cells. Among the enriched angiogenesis-related genes, we observed high expression of KLK5 and L1CAM was mostly associated with poor clinical outcomes in NSCLC patients through Kaplan-Meier survival analysis in a TCGA cohort. Moreover, an independent validation in a cohort of ALTER0303 (NCT02388919) indicated that high serum levels of KLK5 and L1CAM were also associated with poor anlotinib response in NSCLC patients at 3rd line. Lastly, we demonstrated that knockdown of KLK5 and L1CAM increases anlotinib-induced cytotoxicity in anlotinib-resistant NCI-H1975 cells. Collectively, our study suggested serum levels of KLK5 and L1CAM potentially serve as biomarkers for anlotinib-responsive stratification in NSCLC patients at 3rd line.
Highlights
Biomarkers play an important role in therapies of non-small cell lung cancer (NSCLC)
Consistent with the above results, the invasive ability of anlotinib-resistant NCI-H1975 cells was virtually unaffected, cells were exposed to anlotinib (2 μg/ml) for 24 h (Figures 1H–J). These results suggest that anlotinib resistance in NCI-H1975 cells might be attributed to activation/inactivation of tumor survival-related biological processes or signaling pathways
Previous studies have demonstrated that anlotinib prolongs progression free survival (PFS) and overall survival (OS) in refractory advanced NSCLC patients in clinical trials and indicated that anlotinib may play an important role in anti-angiogenesis and proliferation inhibition [10, 12, 23]
Summary
Biomarkers play an important role in therapies of non-small cell lung cancer (NSCLC). Genomic features, such as gene amplification, point mutations, gene over-expression, and chromosomal translocation, have been identified as biomarkers in NSCLC [1]. Precision therapies have dramatically improved progression free survival (PFS) and overall survival (OS) of NSCLC patients whose tumors harbor positive driver gene mutations, such as EGFR (19 Del and L858R) [2], rearranged ROS1 [3], or translocated ALK [4]. Immune checkpoint inhibitors have significantly prolonged PFS and OS in specific advanced NSCLC patients, due to the assessment of PD1/PDL1 expression and tumor mutation burden (TMB) [5,6,7]. Biomarkers for drug-responsive stratification play crucial roles in NSCLC precision therapy
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