NOTCH1 MUTATION FROM ADENOID CYSTIC CARCINOMA FROM THE SALIVARY GLANDS PRESENT A BETTER RESPONSE TO EPI-DRUG THERAPY

Abstract

Adenoid cystic carcinoma from the salivary glands (ACC-SG) is characterized by slow-growing and metastatic potential. Also, they are resistant to chemotherapy, and mutations in NOTCH1 and MYB suggest a poor prognosis. Objective: Here we decided to test the efficiency of a novel histone deacetylase inhibitor (HDACi), entinostat, in patient-derived xenografts (PDX) of ACC-SG (ACCX9, ACCM1, ACCX6). Study Design: PDX tumors were divided into vehicle, entinostat, cisplatin, and entinostat/cisplatin. Then, tumor growth inhibition (TGI) was calculated for each tumor and frozen samples were processed for gene expression using NanoString and key markers using immunofluorescence. Results: All responded to combined therapy of entinostat/cisplatin and the overall TGI observed was 106%, 63%, and 38% for ACCX9, ACCM1, and ACCX6, respectively. Furthermore, we found that tumors with a better response to therapy had a low expression of Ki-67, p16 ink4, gamma-H2 AX, nuclear factor kappa B (NFkB), p300, and upregulation of caspase3, H3 K9, and acetyl-p53. Reduced expression of NOTCH1 was associated with better response to therapy whereas high levels of MYB were associated with reduced response. Conclusion: Overall, a subset of ACC-SG presenting with a NOTCH1 mutation had a better response to the new epigenetic therapy, and that ACC-SG is comprised of a heterogeneous group of tumors exhibiting distinct genetic and resistance behavior toward HDACi. Adenoid cystic carcinoma from the salivary glands (ACC-SG) is characterized by slow-growing and metastatic potential. Also, they are resistant to chemotherapy, and mutations in NOTCH1 and MYB suggest a poor prognosis. Objective: Here we decided to test the efficiency of a novel histone deacetylase inhibitor (HDACi), entinostat, in patient-derived xenografts (PDX) of ACC-SG (ACCX9, ACCM1, ACCX6). Study Design: PDX tumors were divided into vehicle, entinostat, cisplatin, and entinostat/cisplatin. Then, tumor growth inhibition (TGI) was calculated for each tumor and frozen samples were processed for gene expression using NanoString and key markers using immunofluorescence. Results: All responded to combined therapy of entinostat/cisplatin and the overall TGI observed was 106%, 63%, and 38% for ACCX9, ACCM1, and ACCX6, respectively. Furthermore, we found that tumors with a better response to therapy had a low expression of Ki-67, p16 ink4, gamma-H2 AX, nuclear factor kappa B (NFkB), p300, and upregulation of caspase3, H3 K9, and acetyl-p53. Reduced expression of NOTCH1 was associated with better response to therapy whereas high levels of MYB were associated with reduced response. Conclusion: Overall, a subset of ACC-SG presenting with a NOTCH1 mutation had a better response to the new epigenetic therapy, and that ACC-SG is comprised of a heterogeneous group of tumors exhibiting distinct genetic and resistance behavior toward HDACi.