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

Elisabetta Sauta,Valentina Sancisi,Alessia Ciarrocchi,Elena Tagliavini,Massimiliano Paci,Giulia Gobbi,Federica Torricelli,Silvia Strocchi,Davide Ambrosetti,Riccardo Bellazzi,Eleonora Zanetti,Giovanna Damia,Francesca Reggiani,Giacomo Santandrea

doi:10.3390/cancers13143477

Abstract

Simple SummaryThe main histological subtypes of lung cancer are small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). NSCLC is further subdivided into squamous-cell carcinoma (SCC) and adenocarcinoma (AD). Despite the recent introduction of innovative therapies, lung cancer is still the first cause of cancer-related human death, indicating that the discovery of new therapeutic targets is still a compelling need for this disease. In the present work, we performed a functional genomics analysis on different lung cancer histotypes, combining data derived from different omics resources with in vitro validation. Through this approach, we identified and validated CSNK1A1, KDMA2, and LTB4R2 as new druggable vulnerabilities in lung cancer. These results open new possibilities for the development of innovative therapies for lung cancer patients.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.

Highlights

Despite remarkable research efforts and the groundbreaking introduction of targeted therapy and immune therapy, lung cancer is still the leading cause of cancer-related death.the prognosis is still poor, with a five year survival rate of only 17% [1]
We aimed to identify genes that are required for lung cancer cell proliferation and that can be used as new therapeutic targets
We performed CRISPR/Cas9 screening in the A549 cell line, derived from lung adenocarcinoma (Figure 1A and Supplementary Video S1)

Summary

Introduction

Despite remarkable research efforts and the groundbreaking introduction of targeted therapy and immune therapy, lung cancer is still the leading cause of cancer-related death.the prognosis is still poor, with a five year survival rate of only 17% [1]. Despite remarkable research efforts and the groundbreaking introduction of targeted therapy and immune therapy, lung cancer is still the leading cause of cancer-related death. SCLC represents about 13% of cases, whereas NSCLC is further subdivided in various subtypes, the most prevalent of which are adenocarcinoma (AD) (50%) and squamous-cell carcinoma (SCC) (22%) [2,3]. Lung cancer subtypes differ in genetic alterations, carrying distinct sets of mutations and rearrangements [3]. In AD, several drivers of genetic alterations have been identified and mutations on EGFR gene and gene fusions involving ALK or ROS1 genes have been targeted with specific small-molecule inhibitors [4]. Driver mutations have been characterized for SCC and SCLC, the current standard treatment for these patients is platinum-based chemotherapy in combination with immune checkpoint inhibitors [5,6]

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