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

Simple Summary The 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. 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.

[1]  R. Bellazzi,et al.  An integrative functional genomics approach reveals EGLN1 as a novel therapeutic target in KRAS mutated lung adenocarcinoma , 2021, Molecular cancer.

[2]  M. Santarpia,et al.  History of Extensive Disease Small Cell Lung Cancer Treatment: Time to Raise the Bar? A Review of the Literature , 2021, Cancers.

[3]  Caicun Zhou,et al.  The cutting-edge progress of immune-checkpoint blockade in lung cancer , 2020, Cellular & Molecular Immunology.

[4]  Kaushal Parikh,et al.  Changing paradigm in advanced and metastatic non-small cell lung cancer , 2020, Journal of thoracic disease.

[5]  P. Workman,et al.  CHK1 Inhibition Is Synthetically Lethal with Loss of B-Family DNA Polymerase Function in Human Lung and Colorectal Cancer Cells , 2020, Cancer Research.

[6]  G. Castellani,et al.  The Hippo pathway modulates resistance to BET proteins inhibitors in lung cancer cells , 2019, Oncogene.

[7]  Guoan Chen,et al.  Validation of NEDD8-conjugating enzyme UBC12 as a new therapeutic target in lung cancer , 2019, EBioMedicine.

[8]  Joshua M. Korn,et al.  Next-generation characterization of the Cancer Cell Line Encyclopedia , 2019, Nature.

[9]  P. Paik,et al.  New Treatment Options in Advanced Squamous Cell Lung Cancer. , 2019, American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

[10]  Jae-Hong Kim,et al.  Mediatory role of BLT2 in the proliferation of KRAS mutant colorectal cancer cells. , 2019, Biochimica et biophysica acta. Molecular cell research.

[11]  Kendall R. Sanson,et al.  Optimized libraries for CRISPR-Cas9 genetic screens with multiple modalities , 2018, Nature Communications.

[12]  Y. Ben-Neriah,et al.  Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models , 2018, Cell.

[13]  H. Hurwitz,et al.  A Phase I Trial of the IGF-1R Antibody Ganitumab (AMG 479) in Combination with Everolimus (RAD001) and Panitumumab in Patients with Advanced Cancer. , 2018, The oncologist.

[14]  Joshua M. Stuart,et al.  Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer , 2018, Cell.

[15]  Jun Yu Li,et al.  CK1α suppresses lung tumour growth by stabilizing PTEN and inducing autophagy , 2018, Nature Cell Biology.

[16]  David S. Wishart,et al.  DrugBank 5.0: a major update to the DrugBank database for 2018 , 2017, Nucleic Acids Res..

[17]  Alex H. Wagner,et al.  DGIdb 3.0: a redesign and expansion of the drug–gene interaction database , 2017, bioRxiv.

[18]  Ann E. Sizemore,et al.  Computational correction of copy-number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells , 2017, Nature Genetics.

[19]  S. Piana,et al.  Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy , 2017, Oncogene.

[20]  A. Berns,et al.  Drugging the addict: non‐oncogene addiction as a target for cancer therapy , 2016, EMBO reports.

[21]  F. Morgillo,et al.  Therapies in the pipeline for small-cell lung cancer. , 2016, British medical bulletin.

[22]  Jie He,et al.  Epidemiology of Lung Cancer. , 2016, Surgical oncology clinics of North America.

[23]  Joshua M. Korn,et al.  Inhibition of Casein Kinase 1 Alpha Prevents Acquired Drug Resistance to Erlotinib in EGFR-Mutant Non-Small Cell Lung Cancer. , 2015, Cancer research.

[24]  Martin Vingron,et al.  Comprehensive genomic profiles of small cell lung cancer , 2015, Nature.

[25]  A. Whetton,et al.  Molecular histology of lung cancer: from targets to treatments. , 2015, Cancer treatment reviews.

[26]  A. Ciarrocchi,et al.  Histone Deacetylase Inhibitors Repress Tumoral Expression of the Proinvasive Factor RUNX2. , 2015, Cancer research.

[27]  C. Cruciat,et al.  Casein kinase 1 and Wnt/β-catenin signaling. , 2014, Current opinion in cell biology.

[28]  Jung-A Choi,et al.  Ras Promotes Transforming Growth Factor-β (TGF-β)-induced Epithelial-Mesenchymal Transition via a Leukotriene B4 Receptor-2-linked Cascade in Mammary Epithelial Cells* , 2014, The Journal of Biological Chemistry.

[29]  Neville E. Sanjana,et al.  Improved vectors and genome-wide libraries for CRISPR screening , 2014, Nature Methods.

[30]  Aviv Regev,et al.  Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing , 2014, Nature Biotechnology.

[31]  Min Gyu Lee,et al.  Transcriptional Repression of Histone Deacetylase 3 by the Histone Demethylase KDM2A Is Coupled to Tumorigenicity of Lung Cancer Cells* , 2014, The Journal of Biological Chemistry.

[32]  R. Tupler,et al.  Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1). , 2014, American journal of physiology. Regulatory, integrative and comparative physiology.

[33]  Min Gyu Lee,et al.  KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling. , 2013, The Journal of clinical investigation.

[34]  R. Klose,et al.  Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases. , 2012, Journal of medicinal chemistry.

[35]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[36]  S. Robson,et al.  Nucleosome-Interacting Proteins Regulated by DNA and Histone Methylation , 2010, Cell.

[37]  E.Y. Kim,et al.  Ras-induced invasion and metastasis are regulated by a leukotriene B4 receptor BLT2-linked pathway , 2010, Oncogene.

[38]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[39]  Pornpimol Charoentong,et al.  ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks , 2009, Bioinform..

[40]  H. Erdjument-Bromage,et al.  Histone demethylation by a family of JmjC domain-containing proteins , 2006, Nature.

[41]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.