Abstract 2439: Targeting c-fos to suppress metastasis inBRMS1v2germline mutantlung adenocarcinoma
Authors: Liu Yuan , Jones David 
Published: June 2022

Introduction: Approximately 50% of patients with early-stage, surgically resected lung cancer develop distant metastasis. There remains an unmet need to identify patients likely to develop recurrence, and for innovative therapies to decrease this risk.

Methods: The prevalence of single nucleotide polymorphisms (SNPs) rs105266, which causes a missense mutation at codon 273 (Ala to Val) of the metastasis suppressor BRMS1 isoform 2 (BRMS1v2), was assessed using the TCGA cohorts of lung adenocarcinoma (LUAD) and breast cancer, and validated in our LUAD cohort. Next, to explore the function of BRMS1v2 and the impact of BRMS1v2 A273V in LUAD, 3 distinct experimental systems were employed, including 1) Two LUAD cells stably expressing ectopic V5-epitope BRMS1v2 wild type (WT), or A273V mutant, by a retroviral system, 2) LUAD homozygous BRMS1v2A273V/A273V isogenic cells generated via a CRISPR knock-in approach, and 3) patient-derived LUAD organoids (PDO) with homozygous BRMS1v2A273V/A273V. The metastatic capabilities of LUAD cells and PDOs were evaluated by in vitro invasion chamber assays and two in vivo metastasis models: tail-vein injection and intracardiac injection. To interrogate the molecular mechanism of action, RNA-seq. and loss and gain of function experiments using genetic engineering and pharmacological inhibitors were performed.

Results: The homozygous rs1052566 (BRMS1v2A273V/A273V) is present in 8% of individuals of European ancestry and 28% of South Asians. Importantly, BRMS1v2A273V/A273V is associated with an increased risk of metastases and a worse progression-free survival in patients with early-stage disease in the TCGA LUAD cohort (N=278). We mechanistically elucidated that BRMS1v2 A273V abolishes the metastasis suppressor function of BRMS1v2, promoting invasion and metastases. BRMS1v2 A273V fails to interact with nuclear Src, thereby activating intratumoral c-fos. Higher c-fos results in upregulation of CEACAM6, which drives metastases. Using a patient-derived organoid metastasis model, we repurposed a c-fos pharmacologic inhibitor investigated in clinical trials for arthritis and observed suppression of metastases in BRMS1v2A273V/A273V LUAD.

Conclusion: Our data suggest that individuals harboring homozygotic BRMS1v2A273V/A273V have a predisposition for developing metastatic LUAD. Moreover, following external validation, BRMS1v2A273V/A273V could potentially serve as a biomarker to predict the development of metastatic disease in early-stage LUAD. Using a PDO metastasis model we show that pharmacologic targeting of c-fos in BRMS1v2A273V/A273V LUAD results in significantly less metastases in vivo. This offers the first pre-clinical evidence of a targeted therapeutic strategy in LUAD patients with this germline alteration.

Citation Format: Yuan Liu, David Jones. Targeting c-fos to suppress metastasis inBRMS1v2germline mutantlung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2439.