1997P The Akt kinase LANCL2 functions as a key driver in EGFR-mutant lung adenocarcinoma tumorigenesis

Abstract

Epidermal growth factor receptor (EGFR) is a key oncogene in lung adenocarcinoma (LUAD), and resistance to EGFR tyrosine kinase inhibitors is a major obstacle facing EGFR-mutant LUAD patients. We investigated whether the Akt kinase LANCL2 plays a role in promoting EGFR-mutant LUAD cell proliferation and drug resistance. A gene chip array, qPCR validation, and shRNA-based high content screening identified pro-proliferative genes arising from gefitinib+pemetrexed exposure. In silico clinical correlate analysis was performed with the TCGA-LUAD dataset. Cell proliferation, cell cycle arrest, apoptosis, and caspase-3/7 activity assays were performed in EGFR-mutant LUAD cell lines PC9 and HCC827 with shRNA-mediated LANCL2 knockdown or LANCL2 overexpression. A murine xenograft model was used to measure in vivo tumorigenic effects. Pathway and co-IP/MS analyses were employed to identify LANCL2-associated enriched pathways and interactors. LANCL2 positively correlates with EGFR, and LANCL2 gain-of-function is associated with inferior survival, in LUAD patients. LANCL2 knockdown reduced proliferation, induced cell cycle arrest, and enhanced apoptosis in PC9 and HCC827 cells in vitro and suppressed xenograft tumor growth in vivo. LANCL2 overexpression rescued these effects and promoted gefitinib+pemetrexed resistance. Pathway analyses of DEGs from LANCL2 knockdown revealed significant enrichment for several cancer signaling pathways. FLNA and GSTM3 were identified as two novel protein interactors of LANCL2. LANCL2 promotes tumorigenic proliferation, inhibits cell cycle arrest, suppresses apoptosis, and promotes gefitinib+pemetrexed resistance in EGFR-mutant LUAD cells. Based on LANCL2's positive association with EGFR and downstream Akt signaling, LANCL2 may be a promising new therapeutic target for EGFR-mutant LUAD.