Abstract
Rhabdomyosarcomas (RMS) are tumors of the skeletal muscle lineage. Two main features allow for distinction between subtypes: morphology and presence/absence of a translocation between the PAX3 (or PAX7) and FOXO1 genes. The two main subtypes are fusion-positive alveolar RMS (ARMS) and fusion-negative embryonal RMS (ERMS). This review will focus on the role of receptor tyrosine kinases of the human epidermal growth factor receptor (EGFR) family that is comprised EGFR itself, HER2, HER3 and HER4 in RMS onset and the potential therapeutic targeting of receptor tyrosine kinases. EGFR is highly expressed by ERMS tumors and cell lines, in some cases contributing to tumor growth. If not mutated, HER2 is not directly involved in control of RMS cell growth but can be expressed at significant levels. A minority of ERMS carries a HER2 mutation with driving activity on tumor growth. HER3 is frequently overexpressed by RMS and can play a role in the residual myogenic differentiation ability and in resistance to signaling-directed therapy. HER family members could be exploited for therapeutic approaches in two ways: blocking the HER member (playing a driving role for tumor growth with antibodies or inhibitors) and targeting expressed HER members to vehiculate toxins or immune effectors.
Highlights
Published: 16 July 2021Rhabdomyosarcomas (RMS) are tumors of the skeletal muscle lineage, mainly occurring in children and adolescents
HER2 was expressed only by a fraction of RMS, with a slight prevalence for alveolar RMS (ARMS) [38]. Both epidermal growth factor receptor (EGFR) and HER2 were phosphorylated in RMS, while normal skeletal muscle did not show any phosphorylated form of these receptor tyrosine kinases (RTK) [39]
This study suggests that HER2-chimeric antigen receptors (CAR)-T cells could be therapeutic agents against those RMS
Summary
Rhabdomyosarcomas (RMS) are tumors of the skeletal muscle lineage, mainly occurring in children and adolescents. According to the 2020 WHO classification, pediatric RMS can be subdivided into three subtypes: alveolar (ARMS), embryonal (ERMS) and spindle cell/sclerosing (SSRMS) [3]. Fusion-negative RMS have a higher degree of aneuploidy and a heterogeneous mutation burden comprising of coexisting and alternative mutations in RTK/RAS/PI3K pathway. Loss of heterozygosity at 11p15 and activation of RAS pathway are early events in the genesis of fusion-negative RMS [11]. RMS risk stratification is based on postsurgical staging and clinical group classification (as defined by the Intergroup Rhabdomyosarcoma Study) [1]; it takes into account age, site of tumor, presence/absence of node involvement or metastases and incorporates the presence/absence of a fusion event. Sarcoma Group, high risk RMS group comprises stage II–III ERMS at unfavorable site, stage I–III ERMS at
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