Comprehensive Proteomic And Genomic Profiling To Identify Therapeutic Targets In Adenoid Cystic Carcinoma.

6053 Background: Adenoid cystic carcinoma (ACC) is a rare cancer of secretory glands accounting for 10% of salivary gland cancers and 1% of head and neck cancers. ACC rarely responds to chemotherapy or targeted therapy and there is no standard therapy for advanced ACC. Comprehensive molecular profiling of ACC tumors could identify targets of FDA-approved or investigational therapies. Methods: ACC specimens (n = 24) were analyzed with the GPS Cancer test, which includes whole genome sequencing, RNA-seq, and mass spectrometry-based targeted proteomic analysis. Tumor areas of FFPE tissue sections were marked by a pathologist, microdissected and solubilized for mass spectrometric quantitation of 30 clinically relevant proteins. A subset of tumors was further analyzed by global proteomics and compared with results from squamous cell carcinoma of the head and neck (SCCHN). RNA-seq results from ACC tumors was compared with that of various solid tumor types using the k-nearest neighbors algorithm. Results: Targeted proteomic analysis of chemopredictive proteins suggested that 17% of patients were likely to respond to irinotecan, while 33% were likely to be resistant to taxane. The vast majority of patients (96%) did not express any target proteins of FDA-approved targeted therapies. Global proteomic analysis with unsupervised hierarchical clustering of 4,002 proteins from 8 ACC specimens and 6 SCCHN specimens revealed a clear separation between the two groups. In genomic analysis, tumor mutational burden was lower in ACC than in SCCHN (1.53 vs 3.53 per MB). In ACC, MYB-NFIB fusion and missense mutations involved in transcriptional regulation (ZNF43, ZNF519 and ZNF429) were frequent. Expression of CDK6 protein and CDK6 mRNA (transcripts per million) were 4-fold and 3-fold higher in ACC than in SCCHN, respectively. None of the ACC tumors exhibited RB1 deficiency. Among solid tumors, breast cancer was closest to ACC based on mRNA expression. Conclusions: Proteogenomic analysis identified CDK6 overexpression at both protein and mRNA levels in ACC. The combination of CDK6 overexpression and RB1 proficiency suggests that ACC patients may benefit from CDK6 targeted therapy.