Patients with advanced Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung adenocarcinoma are currently treated with standard chemotherapy because of a lack of efficacious targeted therapies. In a translational research study, a group of Spanish investigators from the Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain reasoned that the identification of mediators of Kras signalling in early mouse lung hyperplasias might bypass the difficulties that are imposed by intratumour heterogeneity in advanced tumours, and that it might unveil relevant therapeutic targets. The study results are published in the Nature Medicine.
MEK inhibitors have been tested in KRAS-mutant adenocarcinomas, and a phase III trial with selumetinib is currently recruiting participants. In addition, RAF and ERK inhibitors are undergoing clinical evaluation. Anti-angiogenic compounds such as bevacizumab and nintedanib are approved for use in combination with first- or second-line chemotherapy, respectively. There is an urgent need to develop more efficacious targeted treatments, the investigators wrote in the study background.
Advanced lung adenocarcinomas exhibit substantial intratumor heterogeneity, which is an obstacle to therapeutic success and a source of relapse. It has been proposed that future clinical trials should target founder events in a tumor's phylogeny to decrease chances of relapse.
Therefore, the study researchers used an unbiased approach to identify the effect of oncogenic Kras expression in early mouse hyperplasias that contain fewer than 500 cells. These hyperplasias were assigned to two independent clusters according to gene expression profiling. Despite the early stage of these lesions, the transcriptional profile of the hyperplasias in one cluster was highly similar to a previously established gene expression signature from mouse and human advanced lung adenocarcinomas.
The top-scoring gene in a signature was discoidin domain receptor 1 (Ddr1, encoding DDR1), a tyrosine kinase that is active in various cancers, including lung cancer. Yet, despite reports associating high DDR1 expression levels with poor prognosis in human non-small cell lung cancer, and despite the finding that DDR1 is the most abundantly phosphorylated protein in this tumour type, the potential of DDR1 as a therapeutic target is unknown. In this study, the authors characterised the pro-tumourigenic molecular function of DDR1 and explored its potential as a new therapeutic target for the treatment of advanced KRAS-driven lung adenocarcinoma.
Transcriptional profiling of KrasG12V-driven mouse hyperplasias revealed intertumour diversity with a subset that exhibited an aggressive transcriptional profile analogous to that of advanced human adenocarcinomas. The top-scoring gene in this profile encodes the tyrosine kinase receptor DDR1. The genetic and pharmacological inhibition of DDR1 blocked tumour initiation and tumour progression, respectively.
The concomitant inhibition of both DDR1 and Notch signaling induced the regression of KRAS; TP53-mutant patient-derived lung xenografts with a therapeutic efficacy that was at least comparable to that of standard chemotherapy.
The authors concluded that their data indicate that the combined inhibition of DDR1 and Notch signalling could be an effective targeted therapy for patients with KRAS-mutant lung adenocarcinoma.
Ambrogio C, Gómez-López G, Falcone M, et al. Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma. Nature Medicine 2016; 22:270–277. doi:10.1038/nm.4041