Inhibitor of Differentiation-1 Sustains Mutant KRAS-Driven Progression, Maintenance, and Metastasis of Lung Adenocarcinoma via Regulation of a FOSL1 Network.

Marta Cimavilla Román ,Ignacio I Wistuba,Marta Echavarri-De Miguel,María Collantes,Luis E Raez,Amaia Vilas-Zornoza,Walter Weder,Jae Hwi Jang,Iosune Baraibar,Silvia Cadenas,Inés López,Christian Rolfo,Margarita Ecay,Laura Castro-Labrador,Edgardo S Santos,Simona Taverna,Silvestre Vicent,Ernest Nadal,Ignacio Gil-Bazo,Carmen Behrens,Adrián Vallejo,Mariano Ponz-Sarvisé ,Elizabeth Guruceaga ,David Lara‐Astiaso ,Patxi San Martín-Úriz

doi:10.1158/0008-5472.can-18-1479

Abstract

Because of the refractory nature of mutant KRAS lung adenocarcinoma (LUAD) to current therapies, identification of new molecular targets is essential. Genes with a prognostic role in mutant KRAS LUAD have proven to be potential molecular targets for therapeutic development. Here we determine the clinical, functional, and mechanistic role of inhibitor of differentiation-1 (Id1) in mutant KRAS LUAD. Analysis of LUAD cohorts from TCGA and SPORE showed that high expression of Id1 was a marker of poor survival in patients harboring mutant, but not wild-type KRAS. Abrogation of Id1 induced G2-M arrest and apoptosis in mutant KRAS LUAD cells. In vivo, loss of Id1 strongly impaired tumor growth and maintenance as well as liver metastasis, resulting in improved survival. Mechanistically, Id1 was regulated by the KRAS oncogene through JNK, and loss of Id1 resulted in downregulation of elements of the mitotic machinery via inhibition of the transcription factor FOSL1 and of several kinases within the KRAS signaling network. Our study provides clinical, functional, and mechanistic evidence underscoring Id1 as a critical gene in mutant KRAS LUAD and warrants further studies of Id1 as a therapeutic target in patients with LUAD. SIGNIFICANCE: These findings highlight the prognostic significance of the transcriptional regulator Id1 in KRAS-mutant lung adenocarcinoma and provide mechanistic insight into how it controls tumor growth and metastasis.

Highlights

Lung cancer is the principal cause of cancer-related mortality [1]
OS analysis of patients with lung adenocarcinoma (LUAD) harboring KRAS mutations showed that high inhibitor of differentiation-1 (Id1) expression identified patients with the worst survival outcome (P 1⁄4 0.0106; Fig. 1A), whereas no correlation was observed in wild-type KRAS patients (P 1⁄4 0.7122; Fig. 1B)
To the The Cancer Genome Atlas (TCGA) data set, OS of mutant KRAS patients associated with Id1 expression (P 1⁄4 0.0073; Supplementary Fig. S1A), and no association was observed in patients lacking KRAS mutations (P 1⁄4 0.451; Supplementary Fig. S1B)

Summary

Introduction

The estimated 5-year survival for advanced non–small cell lung cancer (NSCLC) is below 5% [2]. Some patients with NSCLC, such as those with EGFR mutations and ALK or ROS1 rearrangements are susceptible to tailored treatments [3], patients with KRAS mutations, the most frequently mutated oncogene (around 25%), still lack efficient therapies [4]. Recent data illustrate that single genes that are markers of poor survival only in patients with KRAS mutations have a critical role in tumor homeostasis [5,6,7]. KRAS oncogene activation sustains a prooncogenic phenotype involving multiple cancer hallmarks [8]. Different types of stress, including DNA damage/replication stress, proteotoxic, mitotic, metabolic, or oxidative stress, may represent a cellular adaptive process in oncogene activation

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Conclusion