Abstract
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 cancer-related 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.
Highlights
Liposarcoma (LPS) is the most common sarcoma of adults, accounting for 15%–25% of all soft tissue sarcomas (STSs)
We found that receptor tyrosine kinase (RTK) genes were amplified in approximately one-third of Well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS) samples and obtained data suggesting that inhibition of specific Receptor tyrosine kinase (RTK) may become an effective therapeutic option for patients with tumors in which their genes are amplified
We identified a mean of 1.12 (1.05 in WDLPS and 1.16 in DDLPS) potential mutations per patient after single nucleotide polymorphisms (SNPs) elimination (Supplementary Table 2)
Summary
Liposarcoma (LPS) is the most common sarcoma of adults, accounting for 15%–25% of all soft tissue sarcomas (STSs). Of these categories well-differentiated/dedifferentiated LPS (WDLPS/DDLPS) occurs most frequently (48–58% of all LPS) [1,2,3]. Surgical excision remains the standard of care for localized WDLPS/DDLPS, as these tumors are largely resistant to conventional cytotoxic chemotherapy. While lesions located in surgically amenable soft tissue do not recur after complete excision with a clear margin, tumors occurring in deep anatomical sites, such as retroperitoneum, tend to cause death as a result of uncontrolled local recurrence or dedifferentiation and subsequent metastasis. Distant metastases are observed in 15%–20% of cases and they are associated with considerably worse prognosis, with an overall mortality rate of 28%–56% at 5 year follow-up [1, 2, 4]
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