Dissecting the roles of Fra proteins in lung adenocarcinoma

Background

Lung cancer is a life-threatening disease with increased incidence worldwide. Most patients are diagnosed with advanced disease, and as a result, the 5 year survival rate is among the lowest in cancer. Among all lung cancer, 85% are non small lung cancer (NSCLC) subtype, which can be subdivided in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). K-Ras mutation is the most common in NSCLC, but no drugs that target K-Ras directly or indirectly have yet been discovered. Therefore, there is a need to find a druggable target that can help in the treatment of lung cancer patients. Fos-related antigen 2 (Fra-2), a member of AP-1 transcription factors, has been shown to be activated by K-Ras signalling, as well as deregulated in many cancer types.

Methods

Prognosis value of Fra-2 mRNA expression level was assessed in transcriptomic data from 1928 NSCLC patients through an online survival analysis software. We generated a genetic engineered mouse model (GEMM) for Fra-2 inactivation in an experimental model of lung ADC induced by K-Ras mutation (G12V) and p53 inactivation. Fra-2 and p53 inactivation, and mutant K-Ras expression, are induced simultaneously by infection with a Cre-expressing Adenovirus delivered intra-nasally. Development of lung tumours was longitudinally monitored by micro-CT.

Results

Fra-2 mRNA high expression was found to be significantly correlated to poor outcome in this ADC patient cohort. Genetic inactivation of Fra-2 in this lung cancer model prolongs the survival of the mice compared with heterozygous Fra-2 by decreasing tumor incidence, number and volume.

Conclusions

Our results identify a new potential therapeutic target in K-Ras mutated lung ADC.

Clinical trial identification

Legal entity responsible for the study

A. Alfraidi

Funding

World Wide Cancer Research formerly AICR

Disclosure

All authors have declared no conflicts of interest.