Dual Therapy with DDR1 and Notch Inhibitors Kills KRAS-Mutant Lung Tumors

Targeted therapies to treat KRAS-mutant lung adenocarcinomas are lacking. To identify potential therapeutic targets, Ambrogio and colleagues used laser-capture microdissection to perform gene expression analysis on early Kras^G12V expressing mouse lung hyperplasias. The genes clustered into two groups, hyperplasia 1 (H1) and H2, with the H2 profile associated with advanced mouse and human KRAS-mutant lung adenocarcinomas. The top-scoring gene in the H2 signature was the tyrosine kinase discoidin domain receptor 1 (Ddr1). In a lung adenocarcinoma mouse model, Kras^G12V;Ddr1^−/− tumors grew more slowly and had reduced progression to aggressive tumors, compared with Kras^G12V;Ddr1^+/+ tumors, and Ddr1-deficient mice had a 70% survival increase. Similarly, treatment with an oral DDR1 inhibitor reduced the tumor burden in Kras^G12V mice, but did not affect Kras^G12V;Ddr1^−/− tumors. Notch signaling is essential in KRAS-driven lung adenocarcinomas and is activated by DDR1, prompting investigation of the effects of combined inhibition of DDR1 and Notch signaling. Dual treatment was additive and resulted in enhanced apoptosis not only in Kras^G12V tumors, but also in the more aggressive Kras^G12V;Trp53^−/− tumors that were resistant to single-agent treatment. Dual DDR1 and Notch inhibition was as effective as standard-of-care chemotherapy and resulted in less toxicity. Further, in orthotopic patient-derived xenograft models of KRAS-mutant lung adenocarcinoma, combined inhibition of DDR1 and Notch using dasatinib and demcizumab, respectively, resulted in reduced tumor burden compared to chemotherapy-treated mice, with increased tumor necrosis and decreased proliferation. Mechanistically, combined inhibition of DDR1 and Notch signaling suppressed a number of signaling pathways essential for tumor progression and survival, including ERK, AKT, p38, BCL-2, and BCL-xL. Taken together, these results indicate that coinhibition of DDR1 and Notch reduces the growth of KRAS-mutant lung adenocarcinomas and is at least as effective as standard chemotherapy, supporting further clinical investigation of novel Notch and DDR1 inhibitors in KRAS-mutant lung tumors.

Ambrogio C, Gómez-López G, Falcone M, Vidal A, Nadal E, Crosetto N, et al. Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma. Nat Med 2016 Feb 8 [Epub ahead of print].