Abstract
Therapies targeting the tyrosine kinase activity of Epidermal Growth Factor Receptor (EGFR) have been proven to be effective in treating a subset of non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations. Inevitably these patients develop resistance to the EGFR-targeted tyrosine kinase inhibitors (TKIs). Here, we performed integrated genomic analyses using an in vitro system to uncover alternative genomic mechanisms responsible for acquired resistance to EGFR-TKIs. Specifically, we identified 80 genes whose expression is significantly increased in the erlotinib-resistant clones. RNAi-based systematic synthetic lethal screening of these candidate genes revealed that suppression of one upregulated transcript, SCRN1, a secernin family member, restores sensitivity to erlotinib by enhancing inhibition of PI3K/AKT signaling pathway. Furthermore, immunohistochemical analysis revealed increased levels of SCRN1 in 5 of 11 lung tumor specimens from EGFR-TKIs resistant patients. Taken together, we propose that upregulation of SCRN1 is an additional mechanism associated with acquired resistance to EGFR-TKIs and that its suppression serves as a novel therapeutic strategy to overcome drug resistance in these patients.
Highlights
The success of genome-directed small molecule inhibitors targeted against aberrantly activated tyrosine kinases have changed the clinical paradigm of cancer treatments and ushered in the age of precision medicine [1, 2]
Oncogenic epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) patients are of significant clinical importance, the role that the elevated kinase activity associated with mutant EGFR is largely unexplored
We sought to examine: 1) if increased kinase acitivity promotes the onset of acquired resistance to EGFR tyrosine kinase inhibitor erlotinib and 2) how it contributes to resistance mechanisms
Summary
The success of genome-directed small molecule inhibitors targeted against aberrantly activated tyrosine kinases have changed the clinical paradigm of cancer treatments and ushered in the age of precision medicine [1, 2]. We established an erlotinibresistant in vitro model system using PC9 NSCLC cells ectopically overexpressing the exon 19 deletion EGFR mutant and identified genes whose expression is significantly increased or decreased in erlotinib-resistant clones compared to parental cell lines by expression profiling.
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