Molecular Targets in Alveolar Rhabdomyosarcoma: A Narrative Review of Progress and Pitfalls

Abstract

Alveolar rhabdomyosarcoma (ARMS) is a highly aggressive pediatric soft-tissue sarcoma driven by PAX3/7-FOXO1 fusion proteins. Despite intensive multimodal therapy, outcomes remain poor for patients with fusion-positive ARMS. This review integrates recent advances in the molecular pathogenesis of ARMS, highlighting key diagnostic and therapeutic targets. We discuss the central role of fusion proteins in transcriptional reprogramming, impaired myogenic differentiation, and super-enhancer activation. Emerging biomarkers (YAP, TFAP2B, P-cadherin) and oncogenic kinases (Aurora A, CDK4, PLK1) are evaluated alongside receptor tyrosine kinases (FGFR, MET) and transcription factors involved in metabolic rewiring (FOXF1, ETS1). Additionally, we examine immunotherapeutic strategies, epigenetic modifiers, and noncoding RNAs as potential therapeutic avenues. Together, these insights provide a comprehensive framework for developing biomarker-guided, multi-targeted therapies to improve outcomes in ARMS.

Keywords: PAX3-FOXO1; alveolar rhabdomyosarcoma (ARMS); receptor tyrosine kinases; targeted therapy; therapeutic resistance; transcription factors.

Figure 3

TRIB3 integrates PAX3-FOXO1 activity with AKT signaling and FOXO1 suppression in high-risk rhabdomyosarcoma. This schematic illustrates the regulatory network involving TRIB3 in fusion-positive rhabdomyosarcoma (FP-RMS). The fusion oncogene PAX3-FOXO1 transcriptionally upregulates TRIB3, which, in turn, sustains AKT-pathway activation and promotes phosphorylation-mediated survival signals. TRIB3 also reinforces the stability or expression of PAX3-FOXO1, forming a positive feedback loop. Additionally, TRIB3 suppresses the FOXO1 transcription factor, which would otherwise promote stress responses, apoptosis, and chemosensitivity. Through these interactions, TRIB3 shifts the balance away from differentiation and apoptosis toward oncogenic maintenance, transcriptional reprogramming, and chemotherapy resistance in FP-RMS [Based on [168,169,173]]. Green arrows—activation; red arrows—inhibition.

Figure 1

PAX3-FOXO1-mediated transcriptional activation in fusion-positive alveolar rhabdomyosarcoma (ARMS). The schematic illustrates how PAX3-FOXO1 binds enhancer regions and recruits epigenetic regulators such as CHD4, CBP/p300, and BRD4. These interactions drive super-enhancer formation, enhancer–promoter looping via the Mediator complex, and RNA-polymerase-II recruitment. Key target genes, including MYOD1, MYOG, and MYCN, constitute a core transcriptional circuit that sustains the tumorigenic phenotype [39,40]. Key Molecular Players: These comprise PAX3-FOXO1, a fusion oncoprotein with DNA-binding (DNB; DNA binding domain) and transactivation (TAD; transcription factor scaffold domain) functions; CBP/p300, histone acetyltransferases recruited via C793 in FOXO1; BRD4, which binds acetylated histones and facilitates RNA-Pol-II elongation; CHD4, a chromatin remodeler required for PAX3-FOXO1 function; Mediator, which promotes enhancer–promoter communication; TFIID and RNA Pol II, components of the transcription initiation complex; and the target genes: MYOD1, MYOG, MYCN, and FGFR4.

Figure 2

Functional interplay between PAX3-FOXO1, FOXF1, ETS1, and SNAIL in promoting dedifferentiation and therapy resistance in fusion-positive alveolar rhabdomyosarcoma (FP-RMS). The fusion protein PAX3-FOXO1 transcriptionally activates FOXF1, which, in turn, cooperates with ETS1 and SNAIL to repress muscle differentiation and promote therapy resistance in FP-RMS. ETS1 enhances FOXF1 chromatin occupancy and cooperates on shared enhancer elements, while SNAIL contributes to transcriptional repression and mesenchymal-like adaptation. Together, this network forms a differentiation-inhibitory axis downstream of PAX3-FOXO1.