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.

成釉细胞瘤 (AB) 是一种由成釉细胞谱系细胞产生的牙源性肿瘤。虽然相对不常见且很少发生转移，但 AB 肿瘤是局部侵袭性的，对颌骨和周围结构具有破坏性。护理标准的手术切除通常会导致毁容，并且许多肿瘤会局部复发，因此需要越来越具有挑战性的手术。最近对 AB 的基因组研究发现了致癌驱动突变，包括丝裂原活化蛋白激酶 (MAPK) 和 Hedgehog 信号通路。针对这些驱动因素的药物治疗将是非常理想的手术替代方案或补充方案；然而，现有 AB 细胞系的缺乏阻碍了临床转化。为了弥补这一差距，在这里，我们报告了通过“条件重编程”产生的 6 个新 AB 细胞系的建立及其基因组特征，揭示了 FGFR2、KRAS、NRAS、BRAF、PIK3CA 和 SMO 中的驱动突变。此外，在原理验证研究中，我们使用新细胞系来研究 AB 癌基因依赖性和药物敏感性。在我们的研究结果中，具有 KRAS 或 NRAS 突变（MAPK 途径）的 AB 细胞对 MEK 抑制非常敏感，MEK 抑制促进了成釉细胞分化。具有激活 SMO-L412F 突变（Hedgehog 途径）的 AB 细胞对vismodegib 不敏感；然而，一种独特的小分子 SMO 抑制剂 BMS-83​​3923 显着降低了下游 Hedgehog 信号传导和肿瘤细胞活力。