PDGFR-A is a therapeutic target in alveolar rhabdomyosarcoma.
Alveolar rhabdomyosarcoma is an aggressive skeletal muscle cancer of childhood. Our initial studies of rhabdomyosarcoma gene expression for patients enrolled in a national clinical trial suggested that platelet-derived growth factor receptor A (PDGFR-A) may be a mediator of disease progression and metastasis. Using our conditional mouse tumor models that authentically recapitulate the primary mutations and metastatic progression of alveolar rhabdomyosarcomas in humans, we found by immunoblotting and immunokinase assays that PDGFR-A and its downstream effectors, mitogen-activated protein kinase and Akt, were highly activated in both primary and metastatic tumors. Inhibition of PDGFR-A by RNA interference, small molecule inhibitor or neutralizing antibody had a dramatic effect on tumor cell growth both in vitro and in vivo, although resistance evolved in one-third of tumors. These results establish proof-of-principal for PDGFR-A as a therapeutic target in alveolar rhabdomyosarcoma.
Taniguchi
E
E
Greehey Children's Cancer Research Institute, Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
Nishijo
K
K
McCleish
A T
AT
Michalek
J E
JE
Grayson
M H
MH
Infante
A J
AJ
Abboud
H E
HE
Legallo
R D
RD
Qualman
S J
SJ
Rubin
B P
BP
Keller
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019942:Genes, p16; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D018345:Mice, Knockout; D019042:Muscle Neoplasms / Q000188:drug therapy* / Q000209:etiology; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000502:physiology*; D018232:Rhabdomyosarcoma, Alveolar / Q000188:drug therapy* / Q000209:etiology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha