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.
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.
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.
Our results identify a new potential therapeutic target in K-Ras mutated lung ADC.
Clinical trial identification
Legal entity responsible for the study
World Wide Cancer Research formerly AICR
All authors have declared no conflicts of interest.