Genetic Profiling in Heterogeneous High-Grade Adenoid Cystic Carcinoma Identifies NOTCH1 Inhibition as a Therapeutic Strategy

Abstract

Background High-grade adenoid cystic carcinomas (ACCs), consisting mostly of the solid type along with the occasional high-grade transformation (ACC-HGT) type, are highly aggressive and heterogeneous tumors. Because of the rarity of the tumors, therapeutic strategy guided by genetic profiles based on next generation sequencing (NGS) has been not published on these tumors. Results Forty-four tissues microdissected from 36 high-grade ACC cases (31 solid type ACCs and 5 ACC-HGTs) were included in our study. The solid components from the 31 solid ACCs, were enriched for mutations of genes in the NOTCH (NOTCH1, 68%; SPEN 23%) and the chromatin-remodeling pathway and were absent of the myoepithelial cell differentiation. The cases with NOTCH1 mutation exhibited strong NCID expression, which was associated with poor distant metastasis-free survival. BRCA2 mutation was observed in 23% of solid ACCs, conferring sensitivity to PARP inhibitors. From 5 of the solid ACCs, the intratumor heterogeneity was delineated between the cribriform/tubular and the solid components. NOTCH1 and FGFR2 mutations as well as NOTCH2 amplification were restricted to the solid component indicating the clonal selection within the same tumor. From 2 aggressive solid ACCs the subclones evolved in progression for local relapse and distant metastasis, although they manifested close genomic resemblance to primary tumors. Five tumors of ACC-HGTs were characterized by a loss of biphasic ductal-myoepithelial differentiation in HGT area and enriched for alterations in the NOTCH, P53 and PI3K pathways. Guided by the genetic profiles, the preclinical efficiency of a gamma-secretase inhibitor BMS-906024 was evaluated in the ACC patient-derived xenografts (PDXs) models with activating NOTCH1 mutation and it demonstrated robust antitumor effects. Conclusion This is the first report to describe the intratumor heterogeneity within a solid ACC as well as the intertumor evolution of clones among the primary/recurrent/metastatic tumors. Different from conventional ACCs, high-grade ACCs should be approached with a distinct therapeutic strategy particularly targeting NOTCH1 by gamma-secretase inhibitors. Microdissecting the highest grade component guided by histology is a highly recommended tumor sampling strategy and facilitates the detection of key molecular targets.