Identification of downstream signaling cascades of ACK1 and prognostic classifiers in non-small cell lung cancer

Abstract

<i>Activated Cdc42-associated kinase 1</i> (<i>ACK1</i>) is an oncogene in multiple cancers, but the underlying mechanisms of its oncogenic role remain unclear in non-small cell lung cancer (NSCLC). Herein, we comprehensively investigated the ACK1-regulated cell processes and downstream signaling pathways, as well as its prognostic value in NSCLC. We found that <i>ACK1</i> gene amplification was associated with mRNA levels in The Cancer Genome Atlas (TCGA) lung cancer cohort. The Oncomine databases showed significantly elevated <i>ACK1</i> levels in lung cancer. <i>In vitro</i>, an ACK1 inhibitor (dasatinib) increased the sensitivity of NSCLC cell lines to AKT or MEK inhibitors. RNA-sequencing results demonstrated that an <i>ACK1</i> deficiency in A549 cells affected the MAPK, PI3K/AKT, and Wnt pathways. These results were validated by gene set enrichment analysis (GSEA) of data from 188 lung cancer cell lines. Using Cytoscape, we dissected 14 critical ACK1-regulated genes. The signature with the 14 genes and <i>ACK1</i> could significantly dichotomize the TCGA lung cohort regarding overall survival. The prognostic accuracy of this signature was confirmed in five independent lung cancer cohorts and was further validated by a prognostic nomogram. Our study unveiled several downstream signaling pathways for ACK1, and the proposed signature may be a promising prognostic predictor for NSCLC.