1. Skeletal muscle diseases and related rare diseases
Skeletal muscles are essential for movement, breathing, posture, and overall health. Disorders affecting the skeletal muscle tissue are categorized as musculoskeletal and neuromuscular disorders. Musculoskeletal disorders involve injuries and conditions affecting the skeletal muscles and associated connective tissues such as bones and joints. The symptoms of musculoskeletal disorders include pain, stiffness, limited range of motion, inflammation, and fatigue. Musculoskeletal disorders could also contribute to muscle atrophy including muscular dystrophy, osteoarthritis, rheumatoid arthritis, and spinal muscular atrophy. Neuromuscular disorders affect the peripheral nerves that control voluntary muscles or neuromuscular junction. Muscular dystrophy results in wasting and loss of muscle tissue, disability and possible deformity. Treatment for muscle atrophy includes regular exercise, physical therapy, medications managing chronic diseases or addressing nutritional deficiencies. Uncontrolled cell growth arising from bones or muscles will lead to musculoskeletal cancers, which are often rare cancers, such as osteosarcoma, Ewing sarcoma, chondrosarcoma, rhabdomyosarcoma (RMS), leiomyosarcoma. The treatment for musculoskeletal cancer depends on the sizes, stages and locations of the cancers which usually involves surgery, radiotherapy and chemotherapy. Targeted therapy provides more personalized and effective treatment approaches and play an important role in the management of some cancers such as breast cancer, lung cancer and colorectal cancer. Although there is some targeted therapy for osteosarcoma 1 , 2 , much less is available for musculoskeletal cancer compared to other cancer types.
2. Histological subtypes of RMS
RMS is a rare disease, as defined by Genetic and Rare Diseases Information Center (GARD), National Institute of Health (NIH). RMS is the most common type of soft tissue sarcoma that malignant cells arising from skeletal muscle, and it primarily affects children and adolescents. Approximately 350 new cases of RMS are diagnosed every year in the United States. Overall incidence is 4.5-6 cases per million people in Europe and United States and 3.5 cases per million in Asia 3 . Although the overall five-year survival rate for RMS in children exceeds 70%, the five-year survival rate of children with RMS that has metastasized to distant parts of the body is less than 30% and patients with recurrent RMS is only 17% 4 - 6 . Adults with RMS have worse survival than children, with an overall five-year survival rate of only 20% to 40% 7 , 8 .
There are 4 histologic subtypes of RMS classified according to the 5th edition of the World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone: embryonal rhabdomyosarcoma (eRMS), alveolar rhabdomyosarcoma (aRMS), spindle cell/sclerosing rhabdomyosarcoma (scRMS) and pleomorphic rhabdomyosarcoma (pRMS) (Figure 1 A) 9 . The embryonal subtype is the most frequently observed subtype which account for 70% to 75% of childhood RMS. eRMS is associated with round-cell phenotype and typically arises in the head and neck or genitourinary region in children younger than five. Approximately 20% to 25% of children with RMS have the alveolar subtype. Tumors with alveolar histology usually in extremities, trunk, and perineum/perianal region and have an increased frequency in adolescents and young adults 10 . The scRMS are considered in the same diagnosis spectrum and account for 3% to 10% of all cases, with high frequency at the paratesticular site. The pRMS is an extremely rare subtype characterized by a high-grade pleomorphic sarcoma arises in the extremities in adults 9 . This type of RMS often results in poor prognosis. Additionally, RMS has been further characterized based on molecular biology characteristics of fusion proteins paired-box 3-forkhead box O1 (PAX3-FOXO1) or paired-box 7-FOXO1 (PAX7-FOXO1). Here, fusion-positive (FP) and fusion-negative (FN) were defined 6 , 11 . Approximately 80% of patients with the aRMS (16% of all RMS) have chromosomal translocations resulting in FOXO1 gene fusion to PAX3 or PAX7 , which is implicated in a poorer prognosis 12 , 13 . Fusion between DNA binding domain of PAX3/7 and transactivation domain of FOXO1 drives epigenetic changes and alters hundreds of genes transcription. Several studies have implicated that PAX3/7-FOXO1 fusion protein regulates many downstream factors to suppress cell apoptosis (MYCN) 14 , promote cell survival (FGFR4), enhance cell invasion (FGFR4 and IGF2) 15 , 16 , increase cell proliferation and motility (c-MET, IGF1, CXCR4) 17 , 18 , drive myogenic determination and repress myogenic differentiation (MYOD, MYOG) 14 , 19 , 20 (Figure 1 B). These PAX3/7-FOXO1 -mediated genomic instability is strongly associated with a poor prognosis in FP aRMS 20 .
3. Clinical treatments of RMS
Treatment of RMS presents unique challenges due to the scarcity of the disease and various anatomical sites of primary tumor. For optimal management and treatment, patients with RMS require multimodality therapy including surgery, radiation therapy and systemic chemotherapy to ensure receiving ideal treatment, supportive care and rehabilitation to achieve optimal survival and quality of life. 21 - 23 . Optimizing patient care requires tailored treatment decisions regarding surgical and radiotherapeutic options, which must be based on factors such as patient ages, tumor sizes, histological subtypes and the anatomical locations of tumors. If the tumor resection will not cause dysfunction or deformity, surgical resection is performed first before other treatment. If this is not possible, only an initial biopsy is performed. Radiation therapy is often used for RMS patients with metastasis or the tumors that cannot be completely removed surgically. In order to prevent recurrence or metastasis of RMS, chemotherapy is used after surgery and/or radiation therapy. The standard chemotherapy regimen for patients with RMS is the combination of vincristine, actinomycin D, and cyclophosphamide (VAC) in North America 24 . In Europe, the chemotherapy regimen is the combination of ifosfamide, vincristine, and actinomycin D (IVA) 6 . Vincristine binds irreversibly to microtubules and spindle proteins in S phase of the cell cycle and thus interferes with the formation of the mitotic spindle, thereby arresting tumor cells in metaphase. Actinomycin D binds to guanine residues in DNA and blocking the action of DNA-dependent RNA polymerase functions thereby inhibit RNA synthesis. Cyclophosphamide and ifosfamide react with DNA to interfere DNA replication and cell division. There are no significant differences in the clinical outcomes between VAC and IVA regimens 25 . Table 1 listed the ongoing or completed clinical trials related to RMS. Most clinical trials focus on the combination of common chemotherapy drugs, while only limited trials test antibody or T cell transplantation application in RMS.
4. Genetic mutations in patients with RMS
Previous reports have documented the mutations observed in eRMS (28.3%) and aRMS (3.5%) 26 . A wide range of genetic mutations were identified in FN RMS including mutations in NRAS , KRAS , HRAS 27 , TP53 28 , PIK3CA , CTNNB1 26 and FGFR4 29 . These gene mutations in RMS are associated with more aggressive genotypes and poorer outcomes. Multiple mutations within individual tumors in FN RMS are associated with worse event-free survival 30 . Thus, it is critical to further characterize the genetic events underlying RMS in order to develop more effective diagnostic, prognostic and therapeutic strategies. J.F. Shern et al. compared gene mutations between FN and FP RMS patients using a combined cohort of the Children's Oncology Group (COG) and United Kingdom RMS patients (n = 641) 30 (Figure 2 ). A higher frequency of mutations in NRAS , BCOR and NF1 genes was observed in patients with FN RMS while mutations in CDK4 and MYCN are more common in patients with FP RMS. The differential frequency of gene mutations between FN and FP RMS may provide direction in developing personalized medical approaches.
4.1 NRAS and NF1 mutations
The RAS gene encodes a membrane-bound GTPase which cycles between an active GTP-bound state and an inactive GDP-bound state. Three members of RAS family NRAS, (Neuroblastoma Rat Sarcoma Virus), HRAS (Harvey Rat Sarcoma Virus) and KRAS (Kirsten Rat sarcoma virus), that transmit signal transduction to regulate a variety of cellular process such as cell growth, differentiation, survival and apoptosis 31 - 34 . After receptor tyrosine kinase (RTK) engagement, guanine nucleotide exchange factors (GEFs) such as SOS1, SOS2 and RASGRF are recruited to the plasma membrane to regulate RAS activity through the exchange of GDP for GTP on RAS proteins 35 . Conversely, RAS switches to the inactive form catalyzed by GTPase-activating proteins (GAPs), which in turn accelerates the hydrolysis of bound GTP to GDP 36 , 37 . There are two major downstream signaling pathways of RAS including RAF/MEK/ERK (MAPK) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) cascades 38 . The RAS/RAF/MEK/ERK pathway plays a crucial role in cell proliferation, migration and invasion of cancer cells 39 , 40 . Active RAS recruits RAF kinase to the plasma membrane, where RAF is activated. Active RAF then phosphorylates and activates MEK which subsequently activate ERK. Active ERK can translocate to the nucleus and activate transcription factors to regulate cell cycle progression 40 , 41 . PI3K/AKT/mammalian target of rapamycin (mTOR) signaling cascade is also the well-studied downstream pathway of RAS which regulates cell progression, protein synthesis, metabolism and cell survival 42 . RAS activates PI3K signaling which phosphorylates phosphoinositides and generates phosphatidylinositol 3,4,5-triphosphate (PIP3), which activates AKT and its substrates, including mTOR, FOXO or NF-κB. The lipid phosphatase PTEN can negatively regulate the PI3K/AKT pathway by dephosphorylating PIP3 and thus reduces the level of phosphorylated AKT. More than 20 percent of cancers contain mutations of RAS family proteins 43 , and this accounts for 35% in RMS 27 , 44 , 45 . Additionally, hypermethylation of the PTEN promoter is found in 90% of FN RMS tumors 46 . Decreased expression level of PTEN or the mutation of PTEN also present in a subset of FN RMS 30 , 47 , 48 . KRAS mutations are found in approximately 22% of cancers, especially in adenocarcinoma. NRAS mutations present in 8% of tumors with high frequency in melanoma. Only 3% of tumors have HRAS mutations 49 , 50 . The RAS mutant defective in GTP hydrolysis can lead to accumulation of GTP-bound RAS and constitutive RAS activation 51 and increase the affinity of NRAS to RAF-1 52 and PI3K 53 .
NF1 encodes neurofibromin 1 containing a region which is similar to the catalytic domain of GTPase-activating proteins (GAPs) 54 . NF1 stimulates GTPase activity of RAS protein, thereby promoting the formation of inactive RAS-GDP and turning off downstream signaling. Tumors associated with NF1 mutations include glomus tumor 55 , optic glioma 56 , juvenile xanthogranulomas 57 , gastrointestinal stromal tumor 58 and RMS 30 . Inactivating mutations of NF1 results in accumulation of active RAS-GTP leading to constitutive activation of the RAS signaling pathway. Increased active RAS-GTP levels stimulate RAS/RAF/MAPK signaling pathway and PI3K/AKT/mTOR signaling pathway which ultimately cause increased cell proliferation and inhibit cell apoptosis.
Given the high recurrence in cancers such as colorectal cancer, pancreatic cancer and lung cancer, signaling molecules within RAS pathways are potential targets to develop targeted therapeutic strategies. Previous studies have reported small molecules that bind to RAS directly to affect its GTP-GDP regulation 59 , 60 or to inhibit the interaction between RAS and GEFs 61 , 62 . Table 2 lists the ongoing or completed clinical trials that target downstream effectors of RAS pathway in cancers with RAS mutations. Figure 3 summarizes the mutated genes of FN RMS in RAS pathway and the FDA approved drugs applied to target RAS signaling cascades. The USA FDA has approved four MEK inhibitors for cancer treatment including trametinib, binimetinib, selumetinib and cobimetinib. Several RAF inhibitors have been approved by the USA FDA for treating certain cancers including vemurafenib, dabrafenib, encorafenib and tovorafenib. The confirmed tumor response rate of BRAF mutation-positive, unresectable or metastatic melanoma patients is higher with the treatment of trametinib (22%) compared to chemotherapy (8%). The overall response rate of BRAF mutation-positive, unresectable or metastatic melanoma patients is higher with the treatment of binimetinib plus encorafenib (63%) compared to vemurafenib (40%). The overall response rate of BRAF mutation-positive metastatic non-small cell lung cancer patients is higher with the treatment of dabrafenib plus trametinib (61%) compared to dabrafenib monotherapy (27%). Drugs targeting RAS pathway have been applied to patients with BRAF mutation-positive melanoma, glioma or on-small cell lung cancer. Specifically, RAS mutations have been found in approximate 35% of RMS patients especially in FN RMS 27 , 44 , 45 . Thus, targeting RAS pathway may have potential for treating RMS.
4.2 CDK4 mutations
Cyclin-dependent kinases (CDKs) are a family of serine/threonine kinases whose activity depends on a regulatory subunit cyclin and play a crucial role in regulating the cell cycle, apoptosis 63 , gene expression 64 , and cell differentiation 65 . CDK4 conjugates with cyclin D to drive the transition from G1 to S phase during DNA replication. The CDK4-cyclin D complex and phosphorylates the retinoblastoma (RB) protein which then releases the E2F transcription factor to initiate gene expression for DNA synthesis. CDK-interacting protein/kinase inhibitory protein (CIP/KIP) family and inhibitors of CDK4 (INK4) family are cyclin-dependent kinase inhibitors. CIP/KIP family members can either inhibit or promote the activity of all major cell cycle CDK/cyclin complexes depending on their posttranslational modification 66 . INK4 family members are able to bind only to CDK4/6-cyclin D complexes and block the progression of the cell cycle 67 . Deregulation of the CDK4/6-cyclin D-INK-RB pathway has been found in a variety of cancers. Hyperactivated CDK4/6 has been reported in many human cancers as a result of overexpression of cyclin D, inactivation of INK4 and CIP/KIP inhibitors or deletion and/or epigenetic alterations of RB 68 . The FDA approved drugs targeting CDK4/6 are listed in Table 3 . CDK4/6 inhibitors are commonly used to treat subtypes of breast cancer. Only abemaciclib is used as monotherapy while other drugs are generally used in combinatory therapy. In addition to breast cancer, there are some ongoing and completed clinical trials applying CDK4/6 inhibitors to other cancers (Table 4 ).
4.3 BCOR mutations
The BCL6 corepressor (BCOR) was identified as a corepressor interacting with the POZ domain of BCL6. BCOR is a transcription factor which is involved in hematopoiesis, lymphoid development, pluripotency of embryonic stem cells and osteogenic/dentinogenic capacity of mesenchymal stem cells 69 , 70 . BCOR can form polycomb repressive complex 1 (PRC1) with RING1, RYBP, NSPC1 and associates with the lysine demethylase 2B (KDM2B) protein to mediate transcriptional repression through epigenetic modifications of histones 71 , 72 . It is a tumor suppressor gene and its loss-of-function mutation has been reported in both malignant and nonmalignant hematologic diseases and is frequently found in acute myeloid leukemia (AML) patients 73 - 75 . Mutations of BCOR interrupt assembly of a non-canonical PRC1.1 complex by unlinking the enzymatic core from the chromatin-targeting complex. As a result, BCOR-mutated PRC1.1 can localize to chromatin without repressive activity, resulting in epigenetic reprogramming and aberrant transcriptional activation of oncogenic signaling programs 72 . Patients with BCOR mutation have a reduced survival rate and poor prognosis since BCOR mutations have been linked to resistance to certain chemotherapy drugs 74 , 76 . While there aren't currently any drugs specifically targeting BCOR mutations, researchers are exploring targeted therapies based on the mechanisms through which BCOR mutations drive cancer development. Approximately 65% of uterine sarcoma patients with BCOR -rearranged mutations have CDK4 amplification or CDKN2A gene inactivation and multiple genes in the CDK4 pathway are overexpressed in BCOR-CCNB3 -fused sarcomas 77 , 78 , suggesting potential targeted therapeutic implications of CDK4/6 inhibitors in BCOR mutated patients.
4.4 MYCN mutations
The MYCN gene is a member of the MYC oncogene family, which consists of MYCC , MYCN and MYCL . The MYC family plays a crucial role in governing the gene expression related to cell proliferation, differentiation, protein synthesis, metabolism and apoptosis 79 - 81 . MYCN gene encodes a transcription factor N-MYC with a short half-life around 30 min 82 whose stability is related to phosphorylation on specific residues. First, CDK1-cyclin B1 phosphorylates N-MYC at Ser54. Then serine-threonine kinase glycogen synthase kinase 3β (GSK3β) recognizes N-MYC (pSer54) and phosphorylates it at Thr50 subsequently triggering protein phosphatase 2A (PP2A)-dependent dephosphorylation of Ser54. Next, F-box and WD repeat domain-containing 7 (FBXW7) polyubiquitinates N-MYC leading to proteasomal degradation 83 - 85 . When the PI3K/AKT pathway is activated, active phospho-AKT phosphorylates and inactivates GSK3β resulting in stabilization of N-MYC 86 , 87 . The deregulation of MYCN occurs in many kinds of cancers and is related to poor prognosis. Amplification of MYCN has been observed in 17-22% of all neuroblastomas 88 , 89 and 5-50% of medulloblastomas 90 - 92 . Approximately 25% of aRMS cases have amplification of MYCN and 55% of aRMS cases have overexpression of MYCN 93 , 94 . Previous studies also showed amplification or overexpression of MYCN in neuroendocrine prostate cancers, prostate adenocarcinomas, small-cell lung cancers and breast cancer 95 - 98 . These findings of aberrant expression of MYCN in a variety of cancers suggest N-MYC as a therapeutic target.
5. Conclusion and future perspectives
Cancer biomarkers are useful for cancer diagnosis, prognosis, and treatment response. Biomarker testing is an important part of precision medicine such as targeted therapy to tailor treatment plans to an individual patient. The field of targeted therapy in cancer management is rapidly evolving because of new discovery of molecular targets, development of new targeted drugs and exploration of different combination strategies.
RMS is a rare cancer that can start in any soft tissues. The diagnosis is performed by conducting physical exams and scans such as MRI, CT or a bone scan. The first line therapy of RMS involves conventional chemotherapy and radiotherapy that affects all rapidly dividing cells. Developing targeted therapies and immunotherapies would be more specific to RMS and lead to less side effects. Once RMS being diagnosed, genetic testing of PAX-FOXO1 fusion gene would be conducted. The constitutively nuclear-localized PAX-FOXO1 fusion protein drives tumorigenesis and is associated with poor prognosis in FP aRMS by modulating the transcription of several genes such as FGFR4 , IGF2 and C XCR4 . While PAX-FOXO1 fusion gene was observed in 16% of all RMS cases, identifying other gene mutations with a high frequency of occurrence would provide a more comprehensive and efficient therapeutic approach. This review summarizes the potential biomarkers in RMS. A high frequency (15%) of mutations in NRAS , BCOR and NF1 genes were observed in FN RMS while mutations in CDK4 and MYCN are more common in FP RMS. There are several developing drugs and clinical trials targeting to these mutations. If the specific genetic mutation can be detected during early diagnosis, targeted therapy would provide more appropriate and effective personalized treatment for RMS patients.
In addition to targeted therapy, studies also reveal the potential application of immunotherapy in RMS. Specific antigens of RMS were identified as immune markers 99 - 101 . Lavoie RR et al. reported the novel mechanistic insights on the role of B7-H3 in tumor immune evasion and RMS progression 99 . Cell-based immunotherapy using EGFR-CAR NK cell confers high efficiency against chemotherapy-resistant RMS cells 102 . Nonetheless, cancers treated with a single-agent therapy would eventually acquire resistance leading to reduced sensitivity during subsequent treatment lines. The combination of targeted therapy and immunotherapy in RMS may overcome drug resistance and improve the outcomes for patients while reducing the side-effects and providing a long-lasting defense against relapses.
Funding
This study was supported by funding from the National Science and Technology Council, Taiwan (grant # NSTC 113-2320-B-007-006-MY3) and from the National Tsing Hua University, Taiwan (grant # 114QF001E1).
Author contributions
Conceptualization: L.C. and T.-L.K. Writing and editing: L.C. and T.-L.K. Visualization: T.-L.K. All authors contributed to the article approved the submitted version.
1 Adewuyi E Chorya H Muili A Moradeyo A Kayode A Naik A Chemotherapy, immunotherapy, and targeted therapy for osteosarcoma: Recent advancements Crit Rev Oncol Hematol 2025 206 104575 39581243 10.1016/j.critrevonc.2024.104575
2 Hu Z Wen S Huo Z Wang Q Zhao J Wang Z Current Status and Prospects of Targeted Therapy for Osteosarcoma Cells 2022 11 10.3390/cells11213507 PMC9653755 36359903
3 Martin-Giacalone BA Weinstein PA Plon SE Lupo PJ Pediatric Rhabdomyosarcoma: Epidemiology and Genetic Susceptibility J Clin Med 2021 10 10.3390/jcm10092028 PMC8125975 34065162
4 Pappo AS Anderson JR Crist WM Wharam MD Breitfeld PP Hawkins D Survival after relapse in children and adolescents with rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group J Clin Oncol 1999 17 3487 93 10550146 10.1200/JCO.1999.17.11.3487
5 Pappo AS Lyden E Breitfeld P Donaldson SS Wiener E Parham D Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the Children's Oncology Group J Clin Oncol 2007 25 362 9 17264331 10.1200/JCO.2006.07.1720
6 Skapek SX Ferrari A Gupta AA Lupo PJ Butler E Shipley J Rhabdomyosarcoma Nat Rev Dis Primers 2019 5 1 30617281 10.1038/s41572-018-0051-2 PMC7456566
7 Hawkins WG Hoos A Antonescu CR Urist MJ Leung DH Gold JS Clinicopathologic analysis of patients with adult rhabdomyosarcoma Cancer 2001 91 794 803 11241248
8 Sultan I Qaddoumi I Yaser S Rodriguez-Galindo C Ferrari A Comparing adult and pediatric rhabdomyosarcoma in the surveillance, epidemiology and end results program, 1973 to 2005: an analysis of 2,600 patients J Clin Oncol 2009 27 3391 7 19398574 10.1200/JCO.2008.19.7483
9 Board WCoTE. Soft Tissue and Bone Tumours WHO Classification of Tumours, 5th Edition, Volume 3: International Agency for Research on Cancer, 2020; 2020
10 Parham DM Ellison DA Rhabdomyosarcomas in adults and children: an update Arch Pathol Lab Med 2006 130 1454 65 17090187 10.5858/2006-130-1454-RIAACA
11 Shern JF Chen L Chmielecki J Wei JS Patidar R Rosenberg M Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors Cancer Discov 2014 4 216 31 24436047 10.1158/2159-8290.CD-13-0639 PMC4462130
12 Barr FG Smith LM Lynch JC Strzelecki D Parham DM Qualman SJ Examination of gene fusion status in archival samples of alveolar rhabdomyosarcoma entered on the Intergroup Rhabdomyosarcoma Study-III trial: a report from the Children's Oncology Group J Mol Diagn 2006 8 202 8 16645206 10.2353/jmoldx.2006.050124 PMC1867584
13 Dumont SN Lazar AJ Bridge JA Benjamin RS Trent JC PAX3/7-FOXO1 fusion status in older rhabdomyosarcoma patient population by fluorescent in situ hybridization J Cancer Res Clin Oncol 2012 138 213 20 22089931 10.1007/s00432-011-1089-7 PMC3932368
14 Ahn EH Regulation of target genes of PAX3-FOXO1 in alveolar rhabdomyosarcoma Anticancer Res 2013 33 2029 35 23645752
15 Loupe JM Miller PJ Bonner BP Maggi EC Vijayaraghavan J Crabtree JS Comparative transcriptomic analysis reveals the oncogenic fusion protein PAX3-FOXO1 globally alters mRNA and miRNA to enhance myoblast invasion Oncogenesis 2016 5 e246 27454080 10.1038/oncsis.2016.53 PMC4972903
16 Khan J Wei JS Ringner M Saal LH Ladanyi M Westermann F Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks Nat Med 2001 7 673 9 11385503 10.1038/89044 PMC1282521
17 Ayalon D Glaser T Werner H Transcriptional regulation of IGF-I receptor gene expression by the PAX3-FKHR oncoprotein Growth Horm IGF Res 2001 11 289 97 11735247 10.1054/ghir.2001.0244
18 Tomescu O Xia SJ Strezlecki D Bennicelli JL Ginsberg J Pawel B Inducible short-term and stable long-term cell culture systems reveal that the PAX3-FKHR fusion oncoprotein regulates CXCR4, PAX3, and PAX7 expression Lab Invest 2004 84 1060 70 15184910 10.1038/labinvest.3700125
19 Khan J Bittner ML Saal LH Teichmann U Azorsa DO Gooden GC cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene Proc Natl Acad Sci U S A 1999 96 13264 9 10557309 10.1073/pnas.96.23.13264 PMC23936
20 Davicioni E Finckenstein FG Shahbazian V Buckley JD Triche TJ Anderson MJ Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas Cancer Res 2006 66 6936 46 16849537 10.1158/0008-5472.CAN-05-4578
21 Donaldson SS Meza J Breneman JC Crist WM Laurie F Qualman SJ Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma-a report from the IRSG Int J Radiat Oncol Biol Phys 2001 51 718 28 11597814 10.1016/s0360-3016(01)01709-6
22 Little DJ Ballo MT Zagars GK Pisters PW Patel SR El-Naggar AK Adult rhabdomyosarcoma: outcome following multimodality treatment Cancer 2002 95 377 88 12124838 10.1002/cncr.10669
23 Stevens MC Rey A Bouvet N Ellershaw C Flamant F Habrand JL Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology-SIOP Malignant Mesenchymal Tumor 89 J Clin Oncol 2005 23 2618 28 15728225 10.1200/JCO.2005.08.130
24 Pappo AS Shapiro DN Crist WM Maurer HM Biology and therapy of pediatric rhabdomyosarcoma J Clin Oncol 1995 13 2123 39 7636557 10.1200/JCO.1995.13.8.2123
25 Crist WM Anderson JR Meza JL Fryer C Raney RB Ruymann FB Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease J Clin Oncol 2001 19 3091 102 11408506 10.1200/JCO.2001.19.12.3091
26 Shukla N Ameur N Yilmaz I Nafa K Lau CY Marchetti A Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways Clin Cancer Res 2012 18 748 57 22142829 10.1158/1078-0432.CCR-11-2056 PMC3271129
27 Stratton MR Fisher C Gusterson BA Cooper CS Detection of point mutations in N-ras and K-ras genes of human embryonal rhabdomyosarcomas using oligonucleotide probes and the polymerase chain reaction Cancer Res 1989 49 6324 7 2680062
28 Taylor AC Shu L Danks MK Poquette CA Shetty S Thayer MJ P53 mutation and MDM2 amplification frequency in pediatric rhabdomyosarcoma tumors and cell lines Med Pediatr Oncol 2000 35 96 103 10918230 10.1002/1096-911x(200008)35:2<96::aid-mpo2>3.0.co;2-z
29 Taylor JGt Cheuk AT Tsang PS Chung JY Song YK Desai K Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models J Clin Invest 2009 119 3395 407 19809159 10.1172/JCI39703 PMC2769177
30 Shern JF Selfe J Izquierdo E Patidar R Chou HC Song YK Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium J Clin Oncol 2021 39 2859 71 34166060 10.1200/JCO.20.03060 PMC8425837
31 Cox AD Der CJ The dark side of Ras: regulation of apoptosis Oncogene 2003 22 8999 9006 14663478 10.1038/sj.onc.1207111
32 Eisfeld AK Schwind S Hoag KW Walker CJ Liyanarachchi S Patel R NRAS isoforms differentially affect downstream pathways, cell growth, and cell transformation Proc Natl Acad Sci U S A 2014 111 4179 84 24586049 10.1073/pnas.1401727111 PMC3964043
33 McCormick F Ras-related proteins in signal transduction and growth control Mol Reprod Dev 1995 42 500 6 8607982 10.1002/mrd.1080420419
34 Shaulian E Karin M AP-1 in cell proliferation and survival Oncogene 2001 20 2390 400 11402335 10.1038/sj.onc.1204383
35 Buday L Downward J Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor Cell 1993 73 611 20 8490966 10.1016/0092-8674(93)90146-h
36 Bos JL Rehmann H Wittinghofer A GEFs and GAPs: critical elements in the control of small G proteins Cell 2007 129 865 77 17540168 10.1016/j.cell.2007.05.018
37 Lowy DR Willumsen BM Function and regulation of ras Annu Rev Biochem 1993 62 851 91 8352603 10.1146/annurev.bi.62.070193.004223
38 De Luca A Maiello MR D'Alessio A Pergameno M Normanno N The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches Expert Opin Ther Targets 2012 16 Suppl 2 S17 27 10.1517/14728222.2011.639361 22443084
39 Lavoie H Gagnon J Therrien M ERK signalling: a master regulator of cell behaviour, life and fate Nat Rev Mol Cell Biol 2020 21 607 32 32576977 10.1038/s41580-020-0255-7
40 Samson SC Khan AM Mendoza MC ERK signaling for cell migration and invasion Front Mol Biosci 2022 9 998475 36262472 10.3389/fmolb.2022.998475 PMC9573968
41 Mendoza MC Er EE Blenis J The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation Trends Biochem Sci 2011 36 320 8 21531565 10.1016/j.tibs.2011.03.006 PMC3112285
42 Fruman DA Chiu H Hopkins BD Bagrodia S Cantley LC Abraham RT The PI3K Pathway in Human Disease Cell 2017 170 605 35 28802037 10.1016/j.cell.2017.07.029 PMC5726441
43 Malumbres M Barbacid M RAS oncogenes: the first 30 years Nat Rev Cancer 2003 3 459 65 12778136 10.1038/nrc1097
44 Schaaf G Hamdi M Zwijnenburg D Lakeman A Geerts D Versteeg R Silencing of SPRY1 triggers complete regression of rhabdomyosarcoma tumors carrying a mutated RAS gene Cancer Res 2010 70 762 71 20068162 10.1158/0008-5472.CAN-09-2532
45 Nakagawa N Kikuchi K Yagyu S Miyachi M Iehara T Tajiri T Mutations in the RAS pathway as potential precision medicine targets in treatment of rhabdomyosarcoma Biochem Biophys Res Commun 2019 512 524 30 30904164 10.1016/j.bbrc.2019.03.038
46 Seki M Nishimura R Yoshida K Shimamura T Shiraishi Y Sato Y Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma Nat Commun 2015 6 7557 26138366 10.1038/ncomms8557 PMC4506514
47 Zhu B Zhang M Williams EM Keller C Mansoor A Davie JK TBX2 represses PTEN in rhabdomyosarcoma and skeletal muscle Oncogene 2016 35 4212 24 26686089 10.1038/onc.2015.486 PMC4916052
48 Lian YL Chen KW Chou YT Ke TL Chen BC Lin YC PIP3 depletion rescues myoblast fusion defects in human rhabdomyosarcoma cells J Cell Sci 2020 133 10.1242/jcs.240325 32220979
49 Hobbs GA Der CJ Rossman KL RAS isoforms and mutations in cancer at a glance J Cell Sci 2016 129 1287 92 26985062 10.1242/jcs.182873 PMC4869631
50 Prior IA Lewis PD Mattos C A comprehensive survey of Ras mutations in cancer Cancer Res 2012 72 2457 67 22589270 10.1158/0008-5472.CAN-11-2612 PMC3354961
51 Herrmann C Ras-effector interactions: after one decade Curr Opin Struct Biol 2003 13 122 9 12581669 10.1016/s0959-440x(02)00007-6
52 Moodie SA Willumsen BM Weber MJ Wolfman A Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase Science 1993 260 1658 61 8503013 10.1126/science.8503013
53 Sjolander A Yamamoto K Huber BE Lapetina EG Association of p21ras with phosphatidylinositol 3-kinase Proc Natl Acad Sci U S A 1991 88 7908 12 1716764 10.1073/pnas.88.18.7908 PMC52414
54 Xu GF O'Connell P Viskochil D Cawthon R Robertson M Culver M The neurofibromatosis type 1 gene encodes a protein related to GAP Cell 1990 62 599 608 2116237 10.1016/0092-8674(90)90024-9
55 Kumar MG Emnett RJ Bayliss SJ Gutmann DH Glomus tumors in individuals with neurofibromatosis type 1 J Am Acad Dermatol 2014 71 44 8 24685357 10.1016/j.jaad.2014.01.913
56 Tang Y Gutmann DH Neurofibromatosis Type 1-Associated Optic Pathway Gliomas: Current Challenges and Future Prospects Cancer Manag Res 2023 15 667 81 37465080 10.2147/CMAR.S362678 PMC10351533
57 Liy-Wong C Mohammed J Carleton A Pope E Parkin P Lara-Corrales I The relationship between neurofibromatosis type 1, juvenile xanthogranuloma, and malignancy: A retrospective case-control study J Am Acad Dermatol 2017 76 1084 7 28189268 10.1016/j.jaad.2016.12.012
58 Zhang W Hu X Chen Z Lai C Case report: Neurofibromatosis type 1 gastrointestinal stromal tumor and small bowel adenocarcinoma with a novel germline NF1 frameshift mutation Front Oncol 2022 12 1052799 36620543 10.3389/fonc.2022.1052799 PMC9815498
59 Hunter JC Gurbani D Ficarro SB Carrasco MA Lim SM Choi HG In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C Proc Natl Acad Sci U S A 2014 111 8895 900 24889603 10.1073/pnas.1404639111 PMC4066474
60 Ostrem JM Peters U Sos ML Wells JA Shokat KM K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions Nature 2013 503 548 51 24256730 10.1038/nature12796 PMC4274051
61 Maurer T Garrenton LS Oh A Pitts K Anderson DJ Skelton NJ Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity Proc Natl Acad Sci U S A 2012 109 5299 304 22431598 10.1073/pnas.1116510109 PMC3325706
62 Sun Q Burke JP Phan J Burns MC Olejniczak ET Waterson AG Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation Angew Chem Int Ed Engl 2012 51 6140 3 22566140 10.1002/anie.201201358 PMC3620661
63 Golsteyn RM Cdk1 and Cdk2 complexes (cyclin dependent kinases) in apoptosis: a role beyond the cell cycle Cancer Lett 2005 217 129 38 15617830 10.1016/j.canlet.2004.08.005
64 Fisher RP CDK regulation of transcription by RNAP II: Not over 'til it's over? Transcription 2017 8 81 90 28005463 10.1080/21541264.2016.1268244 PMC5423476
65 Hydbring P Malumbres M Sicinski P Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases Nat Rev Mol Cell Biol 2016 17 280 92 27033256 10.1038/nrm.2016.27 PMC4841706
66 Csergeova L Krbusek D Janostiak R CIP/KIP and INK4 families as hostages of oncogenic signaling Cell Div 2024 19 11 38561743 10.1186/s13008-024-00115-z PMC10985988
67 Canepa ET Scassa ME Ceruti JM Marazita MC Carcagno AL Sirkin PF INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions IUBMB Life 2007 59 419 26 17654117 10.1080/15216540701488358
68 Deshpande A Sicinski P Hinds PW Cyclins and cdks in development and cancer: a perspective Oncogene 2005 24 2909 15 15838524 10.1038/sj.onc.1208618
69 Fan Z Yamaza T Lee JS Yu J Wang S Fan G BCOR regulates mesenchymal stem cell function by epigenetic mechanisms Nat Cell Biol 2009 11 1002 9 19578371 10.1038/ncb1913 PMC2752141
70 Kelly MJ So J Rogers AJ Gregory G Li J Zethoven M Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis Nat Commun 2019 10 1347 30902969 10.1038/s41467-019-09250-6 PMC6430802
71 Gearhart MD Corcoran CM Wamstad JA Bardwell VJ Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets Mol Cell Biol 2006 26 6880 9 16943429 10.1128/MCB.00630-06 PMC1592854
72 Schaefer EJ Wang HC Karp HQ Meyer CA Cejas P Gearhart MD BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes Blood Cancer Discov 2022 3 116 35 35015684 10.1158/2643-3230.BCD-21-0115 PMC9414116
73 Grossmann V Tiacci E Holmes AB Kohlmann A Martelli MP Kern W Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype Blood 2011 118 6153 63 22012066 10.1182/blood-2011-07-365320
74 Honda A Koya J Yoshimi A Miyauchi M Taoka K Kataoka K Loss-of-function mutations in BCOR contribute to chemotherapy resistance in acute myeloid leukemia Exp Hematol 2021 101-102 42 8 e11 34333045 10.1016/j.exphem.2021.07.005
75 Kang JH Lee SH Lee J Choi M Cho J Kim SJ The mutation of BCOR is highly recurrent and oncogenic in mature T-cell lymphoma BMC Cancer 2021 21 82 33468080 10.1186/s12885-021-07806-8 PMC7816311
76 Hu D Shen K Guo Y Bao XB Dong N Chen S The clinical implications of BCOR mutations in a large cohort of acute myeloid leukemia patients: a 5-year single-center retrospective study Leuk Lymphoma 2024 65 1964 73 39126311 10.1080/10428194.2024.2387730
77 Lin DI Hemmerich A Edgerly C Duncan D Severson EA Huang RSP Genomic profiling of BCOR-rearranged uterine sarcomas reveals novel gene fusion partners, frequent CDK4 amplification and CDKN2A loss Gynecol Oncol 2020 157 357 66 32156473 10.1016/j.ygyno.2020.02.024
78 Tramontana TF Marshall MS Helvie AE Schmitt MR Ivanovich J Carter JL Sustained Complete Response to Palbociclib in a Refractory Pediatric Sarcoma With BCOR-CCNB3 Fusion and Germline CDKN2B Variant JCO Precis Oncol 2020 4 10.1200/PO.19.00258 PMC7446459 32923894
79 Bretones G Delgado MD Leon J Myc and cell cycle control Biochim Biophys Acta 2015 1849 506 16 24704206 10.1016/j.bbagrm.2014.03.013
80 Conacci-Sorrell M Eisenman RN Post-translational control of Myc function during differentiation Cell Cycle 2011 10 604 10 21293188 10.4161/cc.10.4.14794 PMC3173997
81 McMahon SB MYC and the control of apoptosis Cold Spring Harb Perspect Med 2014 4 a014407 24985130 10.1101/cshperspect.a014407 PMC4066641
82 Cohn SL Salwen H Quasney MW Ikegaki N Cowan JM Herst CV Prolonged N-myc protein half-life in a neuroblastoma cell line lacking N-myc amplification Oncogene 1990 5 1821 7 2284101
83 Bonvini P Nguyen P Trepel J Neckers LM In vivo degradation of N-myc in neuroblastoma cells is mediated by the 26S proteasome Oncogene 1998 16 1131 9 9528855 10.1038/sj.onc.1201625
84 Otto T Horn S Brockmann M Eilers U Schuttrumpf L Popov N Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma Cancer Cell 2009 15 67 78 19111882 10.1016/j.ccr.2008.12.005
85 Sjostrom SK Finn G Hahn WC Rowitch DH Kenney AM The Cdk1 complex plays a prime role in regulating N-myc phosphorylation and turnover in neural precursors Dev Cell 2005 9 327 38 16139224 10.1016/j.devcel.2005.07.014
86 Chesler L Schlieve C Goldenberg DD Kenney A Kim G McMillan A Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma Cancer Res 2006 66 8139 46 16912192 10.1158/0008-5472.CAN-05-2769 PMC2924674
87 Kenney AM Widlund HR Rowitch DH Hedgehog and PI-3 kinase signaling converge on Nmyc1 to promote cell cycle progression in cerebellar neuronal precursors Development 2004 131 217 28 14660435 10.1242/dev.00891
88 Brodeur GM Neuroblastoma: biological insights into a clinical enigma Nat Rev Cancer 2003 3 203 16 12612655 10.1038/nrc1014
89 Campbell K Naranjo A Hibbitts E Gastier-Foster JM Bagatell R Irwin MS Association of heterogeneous MYCN amplification with clinical features, biological characteristics and outcomes in neuroblastoma: A report from the Children's Oncology Group Eur J Cancer 2020 133 112 9 32492633 10.1016/j.ejca.2020.04.007 PMC7295664
90 Aldosari N Bigner SH Burger PC Becker L Kepner JL Friedman HS MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children's Oncology Group Arch Pathol Lab Med 2002 126 540 4 11958658 10.5858/2002-126-0540-MAMOAI
91 Behdad A Perry A Central nervous system primitive neuroectodermal tumors: a clinicopathologic and genetic study of 33 cases Brain Pathol 2010 20 441 50 19725831 10.1111/j.1750-3639.2009.00314.x PMC8094730
92 Gessi M von Bueren A Treszl A zur Muhlen A Hartmann W Warmuth-Metz M MYCN amplification predicts poor outcome for patients with supratentorial primitive neuroectodermal tumors of the central nervous system Neuro Oncol 2014 16 924 32 24470553 10.1093/neuonc/not302 PMC4057132
93 Tonelli R McIntyre A Camerin C Walters ZS Di Leo K Selfe J Antitumor activity of sustained N-myc reduction in rhabdomyosarcomas and transcriptional block by antigene therapy Clin Cancer Res 2012 18 796 807 22065083 10.1158/1078-0432.CCR-11-1981
94 Williamson D Lu YJ Gordon T Sciot R Kelsey A Fisher C Relationship between MYCN copy number and expression in rhabdomyosarcomas and correlation with adverse prognosis in the alveolar subtype J Clin Oncol 2005 23 880 8 15681534 10.1200/JCO.2005.11.078
95 Beltran H Rickman DS Park K Chae SS Sboner A MacDonald TY Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets Cancer Discov 2011 1 487 95 22389870 10.1158/2159-8290.CD-11-0130 PMC3290518
96 Nau MM Brooks BJ Jr Carney DN Gazdar AF Battey JF Sausville EA Human small-cell lung cancers show amplification and expression of the N-myc gene Proc Natl Acad Sci U S A 1986 83 1092 6 2869482 10.1073/pnas.83.4.1092 PMC323017
97 Funa K Steinholtz L Nou E Bergh J Increased expression of N-myc in human small cell lung cancer biopsies predicts lack of response to chemotherapy and poor prognosis Am J Clin Pathol 1987 88 216 20 3039835 10.1093/ajcp/88.2.216
98 Mizukami Y Nonomura A Takizawa T Noguchi M Michigishi T Nakamura S N-myc protein expression in human breast carcinoma: prognostic implications Anticancer Res 1995 15 2899 905 8669886
99 Lavoie RR Gargollo PC Ahmed ME Kim Y Baer E Phelps DA Surfaceome Profiling of Rhabdomyosarcoma Reveals B7-H3 as a Mediator of Immune Evasion Cancers (Basel) 2021 13 10.3390/cancers13184528 PMC8466404 34572755
100 Timpanaro A Piccand C Uldry AC Bode PK Dzhumashev D Sala R Surfaceome Profiling of Cell Lines and Patient-Derived Xenografts Confirm FGFR4, NCAM1, CD276, and Highlight AGRL2, JAM3, and L1CAM as Surface Targets for Rhabdomyosarcoma Int J Mol Sci 2023 24 10.3390/ijms24032601 PMC9917031 36768928
101 Orentas RJ Yang JJ Wen X Wei JS Mackall CL Khan J Identification of cell surface proteins as potential immunotherapy targets in 12 pediatric cancers Front Oncol 2012 2 194 23251904 10.3389/fonc.2012.00194 PMC3523547
102 Reindl LM Jalili L Bexte T Harenkamp S Thul S Hehlgans S Precision targeting of rhabdomyosarcoma by combining primary CAR NK cells and radiotherapy J Immunother Cancer 2025 13 10.1136/jitc-2024-011330 PMC12232460 40623716