CSNK1A1, KDM2A, and LTB4R2 Are New Druggable Vulnerabilities in Lung Cancer

Abstract

Lung cancer is the leading cause of cancer-related human death. It is a heterogeneous disease, classified in two main histotypes, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), which is further subdivided into squamous-cell carcinoma (SCC) and adenocarcinoma (AD) subtypes. Despite the introduction of innovative therapeutics, mainly designed to specifically treat AD patients, the prognosis of lung cancer remains poor. In particular, available treatments for SCLC and SCC patients are currently limited to platinum-based chemotherapy and immune checkpoint inhibitors. In this work, we used an integrative approach to identify novel vulnerabilities in lung cancer. First, we compared the data from a CRISPR/Cas9 dependency screening performed in our laboratory with Cancer Dependency Map Project data, essentiality comprising information on 73 lung cancer cell lines. Next, to identify relevant therapeutic targets, we integrated dependency data with pharmacological data and TCGA gene expression information. Through this analysis, we identified CSNK1A1, KDM2A, and LTB4R2 as relevant druggable essentiality genes in lung cancer. We validated the antiproliferative effect of genetic or pharmacological inhibition of these genes in two lung cancer cell lines. Overall, our results identified new vulnerabilities associated with different lung cancer histotypes, laying the basis for the development of new therapeutic strategies.

The pancancer overexpressed NFYC Antisense 1 controls cell cycle mitotic progression through in cis and in trans modes of action

“…E Heatmap reporting NES (FDR < 0.10) of cancer hallmarks (GSEA) for genes ranked for correlation with NFYC-AS1 in LUSC cells (CCLE). F GSEA plots of genes related to lung cancer vulnerabilities [ 34 ] or G synthetic lethal in RB1 -mut cells [ 35 ] in genes modulated upon NFYC-AS1 Gapmer-silencing. H Bar plot showing NFYC-AS1 expression (qRT-PCR) at 48 h after 25 nM Gapmer transfection in H82 RB1 -mut cells.…”

“…Interestingly, genes downregulated upon NFYC-AS1 knockdown were enriched in possible actionable therapeutic targets for all lung cancer histotypes, as identified from DepMap vulnerabilities [ 34 ] (Fig. 4F ).…”