Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of dental research	101	12	2022 Nov	1517-1525	J Dent Res

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.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

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
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
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