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Ref Type Journal Article
PMID (35689405)
Authors Nguyen J, Saffari PS, Pollack AS, Vennam S, Gong X, West RB, Pollack JR
Title New Ameloblastoma Cell Lines Enable Preclinical Study of Targeted Therapies.
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS Q61K ameloblastoma sensitive GDC-0623 Preclinical - Cell culture Actionable In a preclinical study, GDC-0623 inhibited Erk phosphorylation and viability of an ameloblastoma cell line harboring NRAS Q61K in culture (PMID: 35689405). 35689405
BRAF V600E ameloblastoma sensitive Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) inhibited viability of ameloblastoma cell lines harboring BRAF V600E in culture (PMID: 35689405). 35689405
NRAS Q61R ameloblastoma sensitive GDC-0623 Preclinical - Cell culture Actionable In a preclinical study, GDC-0623 inhibited Erk phosphorylation and viability of an ameloblastoma cell line harboring NRAS Q61R in culture (PMID: 35689405). 35689405