title: Potential advantages of CUDC-101, a multitargeted HDAC, EGFR, and HER2 inhibitor, in treating drug resistance and preventing cancer cell migration and invasion.
abstract: CUDC-101 is a novel, small-molecule, anticancer agent targeting histone deacetylase (HDAC), EGF receptor (EGFR), and HER2. It is currently in phase I clinical development in patients with solid tumors. Previously, we reported that CUDC-101 has potent antiproliferative and proapoptotic activity in cultured tumor cells and in vivo xenograft models. We now show that cancer cells that have acquired resistance to single-target EGFR inhibitors through upregulation of AXL or loss of E-cadherin remain sensitive to CUDC-101, which inhibits MET- and AXL-mediated signaling, restores E-cadherin expression, and reduces cell migration. CUDC-101 also efficiently inhibited the proliferation of MET-overexpressing non-small cell lung cancer and gastric cancer cell lines and inhibited the migration and invasion of invasive tumor cells. Taken together, these results suggest that coupling HDAC and HER2 inhibitory activities to an EGFR inhibitor may potentially be effective in overcoming drug resistance and preventing cancer cell migration.
authors.affiliation: Curis, Inc., Lexington, MA 02421, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Natalie W
authors.initials: NW
authors.lastname: Pursell
authors.forename: Maria Elena S
authors.initials: ME
authors.lastname: Samson
authors.forename: Ruzanna
authors.initials: R
authors.lastname: Atoyan
authors.forename: Anna W
authors.initials: AW
authors.lastname: Ma
authors.forename: Abdelkader
authors.initials: A
authors.lastname: Selmi
authors.forename: Wanlu
authors.initials: W
authors.lastname: Xu
authors.forename: Xiong
authors.initials: X
authors.lastname: Cai
authors.forename: Maurizio
authors.initials: M
authors.lastname: Voi
authors.forename: Pierre
authors.initials: P
authors.lastname: Savagner
authors.forename: Cheng-Jung
authors.initials: CJ
authors.lastname: Lai
mesh_terms: D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D011799:Quinazolines / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D015820:Cadherins; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D019859:Proto-Oncogene Proteins c-met; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C549566:7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C491743:MET protein, human