TY - JOUR
T1 - Frequent amplification of receptor tyrosine kinase genes in welldifferentiated/ dedifferentiated liposarcoma
AU - Asano, Naofumi
AU - Yoshida, Akihiko
AU - Mitani, Sachiyo
AU - Kobayashi, Eisuke
AU - Shiotani, Bunsyo
AU - Komiyama, Motokiyo
AU - Fujimoto, Hiroyuki
AU - Chuman, Hirokazu
AU - Morioka, Hideo
AU - Matsumoto, Morio
AU - Nakamura, Masaya
AU - Kubo, Takashi
AU - Kato, Mamoru
AU - Kohno, Takashi
AU - Kawai, Akira
AU - Kondo, Tadashi
AU - Ichikawa, Hitoshi
PY - 2017
Y1 - 2017
N2 - Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are closely related tumors commonly characterized by MDM2/CDK4 gene amplification, and lack clinically effective treatment options when inoperable. To identify novel therapeutic targets, we performed targeted genomic sequencing analysis of 19 WDLPS and 37 DDLPS tumor samples using a panel of 104 cancerrelated genes (NCC oncopanel v3) developed specifically for genomic testing to select suitable molecular targeted therapies. The results of this analysis indicated that these sarcomas had very few gene mutations and a high frequency of amplifications of not only MDM2 and CDK4 but also other genes. Potential driver mutations were found in only six (11%) samples; however, gene amplification events (other than MDM2 and CDK4 amplification) were identified in 30 (54%) samples. Receptor tyrosine kinase (RTK) genes in particular were amplified in 18 (32%) samples. In addition, growth of a WDLPS cell line with IGF1R amplification was suppressed by simultaneous inhibition of CDK4 and IGF1R, using palbociclib and NVP-AEW541, respectively. Combination therapy with CDK4 and RTK inhibitors may be an effective therapeutic option for WDLPS/DDLPS patients with RTK gene amplification.
AB - Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are closely related tumors commonly characterized by MDM2/CDK4 gene amplification, and lack clinically effective treatment options when inoperable. To identify novel therapeutic targets, we performed targeted genomic sequencing analysis of 19 WDLPS and 37 DDLPS tumor samples using a panel of 104 cancerrelated genes (NCC oncopanel v3) developed specifically for genomic testing to select suitable molecular targeted therapies. The results of this analysis indicated that these sarcomas had very few gene mutations and a high frequency of amplifications of not only MDM2 and CDK4 but also other genes. Potential driver mutations were found in only six (11%) samples; however, gene amplification events (other than MDM2 and CDK4 amplification) were identified in 30 (54%) samples. Receptor tyrosine kinase (RTK) genes in particular were amplified in 18 (32%) samples. In addition, growth of a WDLPS cell line with IGF1R amplification was suppressed by simultaneous inhibition of CDK4 and IGF1R, using palbociclib and NVP-AEW541, respectively. Combination therapy with CDK4 and RTK inhibitors may be an effective therapeutic option for WDLPS/DDLPS patients with RTK gene amplification.
KW - Dedifferentiated liposarcoma
KW - Liposarcoma
KW - Next-generation sequencing
KW - Receptor tyrosine kinase
KW - Well-differentiated liposarcoma
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U2 - 10.18632/oncotarget.14652
DO - 10.18632/oncotarget.14652
M3 - Article
AN - SCOPUS:85013460230
SN - 1949-2553
VL - 8
SP - 12941
EP - 12952
JO - Oncotarget
JF - Oncotarget
IS - 8
ER -
