New Ameloblastoma Cell Lines Enable Preclinical Study of Targeted Therapies

Ameloblastoma (AB) is an odontogenic tumor that arises from ameloblast-lineage cells. Although relatively uncommon and rarely metastatic, AB tumors are locally invasive and destructive to the jawbone and surrounding structures. Standard-of-care surgical resection often leads to disfigurement, and many tumors will locally recur, necessitating increasingly challenging surgeries. Recent genomic studies of AB have uncovered oncogenic driver mutations, including in the mitogen-activated protein kinase (MAPK) and Hedgehog signaling pathways. Medical therapies targeting those drivers would be a highly desirable alternative or addition to surgery; however, a paucity of existing AB cell lines has stymied clinical translation. To bridge this gap, here we report the establishment of 6 new AB cell lines-generated by conditional reprogramming-and their genomic characterization that reveals driver mutations in FGFR2, KRAS, NRAS, BRAF, PIK3CA, and SMO. Furthermore, in proof-of-principle studies, we use the new cell lines to investigate AB oncogene dependency and drug sensitivity. Among our findings, AB cells with KRAS or NRAS mutation (MAPK pathway) are exquisitely sensitive to MEK inhibition, which propels ameloblast differentiation. AB cells with activating SMO-L412F mutation (Hedgehog pathway) are insensitive to vismodegib; however, a distinct small-molecule SMO inhibitor, BMS-833923, significantly reduces both downstream Hedgehog signaling and tumor cell viability. The novel cell line resource enables preclinical studies and promises to speed the translation of new molecularly targeted therapies for the management of ameloblastoma and related odontogenic neoplasms.

Automated summary

In this study, six new cell lines of ameloblastoma were established and their genomic characteristics were analyzed. The driver mutations in FGFR2, KRAS, NRAS, BRAF, PIK3CA, and SMO were identified. The new cell lines were used to investigate the oncogene dependency and drug sensitivity of ameloblastoma. It was found that ameloblastoma cells with KRAS or NRAS mutation were highly sensitive to MEK inhibition, promoting ameloblast differentiation. Additionally, AB cells with activating SMO-L412F mutation were insensitive to vismodegib but significantly reduced tumor cell viability when treated with a small-molecule SMO inhibitor, BMS-833923. This novel cell line resource enables preclinical studies and can accelerate the translation of new molecularly targeted therapies for the management of ameloblastoma and related odontogenic neoplasms.