Integrative network analysis of early-stage lung adenocarcinoma identifies aurora kinase inhibition as interceptor of invasion and progression

• Published in: Nature communications 2022-03, Vol.13 (1), p.1592-1592, Article 1592
• Main Authors: Yoo, Seungyeul, Sinha, Abhilasha, Yang, Dawei, Altorki, Nasser K., Tandon, Radhika, Wang, Wenhui, Chavez, Deebly, Lee, Eunjee, Patel, Ayushi S., Sato, Takashi, Kong, Ranran, Ding, Bisen, Schadt, Eric E., Watanabe, Hideo, Massion, Pierre P., Borczuk, Alain C., Zhu, Jun, Powell, Charles A.
• Format: Article
• Language: English
• Subjects: 13/106; 13/51; 38/39; 38/91; 45; 59; 631/553/2711; 631/67/1612/1350; 631/67/322; 631/67/69; 64/60; 692/4028/67/1612/1350; Adenocarcinoma; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - pathology; Animal models; Animals; Aurora kinase; Aurora Kinases; Histology; Humanities and Social Sciences; Humans; Invasiveness; Kinases; Lung cancer; Lung Neoplasms - pathology; Macrolides; Metastases; Mice; multidisciplinary; Network analysis; Perturbation; Phenotypes; Science; Science (multidisciplinary); Therapeutic targets; Tumor cell lines; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29230-7

Here we focus on the molecular characterization of clinically significant histological subtypes of early-stage lung adenocarcinoma (esLUAD), which is the most common histological subtype of lung cancer. Within lung adenocarcinoma, histology is heterogeneous and associated with tumor invasion and diverse clinical outcomes. We present a gene signature distinguishing invasive and non-invasive tumors among esLUAD. Using the gene signatures, we estimate an Invasiveness Score that is strongly associated with survival of esLUAD patients in multiple independent cohorts and with the invasiveness phenotype in lung cancer cell lines. Regulatory network analysis identifies aurora kinase as one of master regulators of the gene signature and the perturbation of aurora kinases in vitro and in a murine model of invasive lung adenocarcinoma reduces tumor invasion. Our study reveals aurora kinases as a therapeutic target for treatment of early-stage invasive lung adenocarcinoma. The molecular factors that drive invasiveness and metastasis in lung adenocarcinoma (LUAD) are not completely understood. Here, the authors use an integrative network approach to identify a gene signature of invasiveness in LUAD, and reveal Aurora kinases as master regulators of invasion.