Disease Information

General Information of the Disease (ID: DIS00199)

• Name: Rhabdomyosarcoma
• ICD: ICD-11: 2B55

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Sensitive Disease: Embryonal rhabdomyosarcoma [ICD-11: 2B55.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MAST111 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: MAST139 cells; Embryo; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: NPE inhibited the activity of ABCB1. Upon 1h combination treatment of MAST139 cells with Vinblastine and 100 ug/ml of NPE , a 40% increase in doxorubicin retention was observed.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Sensitive Disease: Alveolar rhabdomyosarcoma [ICD-11: 2B55.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: RH4 cells; Embryo; Homo sapiens (Human); CVCL_C357
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: NPE inhibited the activity of ABCB1. Upon 1h combination treatment of MAST139 cells with Vinblastine and 100 ug/ml of NPE , a 40% increase in doxorubicin retention was observed.

Larotrectinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tropomyosin-related kinase A (TrkA) [2]

• Resistant Disease: Metastatic undifferentiated sarcoma [ICD-11: 2B55.Y]
• Molecule Alteration: Missense mutation; p.G595R
• Resistant Drug: Larotrectinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NTHY-ORI-3-1 cells; Thyroid gland; Homo sapiens (Human); CVCL_2659
• Mechanism Description: After 6 months on study, restaging scans identified an isolated area of progression in the right hepatic lobe, which was resected (S3), followed by resumption of larotrectinib. NGS from S3 identified an NTRK1 G595R solvent-front mutation. Three months later, diffuse disease was noted on restaging scans.

Preclinical Drug(s) 1 drug(s) in total

Alpelisib/Binimetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [3]

• Sensitive Disease: Alveolar rhabdomyosarcoma [ICD-11: 2B55.0]
• Molecule Alteration: Missense mutation; p.Q61H (c.183A>T)
• Sensitive Drug: Alpelisib/Binimetinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: RAF/MEK/ERK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: RMS cells; Soft tissue; Homo sapiens (Human); CVCL_W527
• In Vivo Model: Chorioallantoic membrane; Gallus gallus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay; FACS; crystal violet staining
• Mechanism Description: Coinhibition of NRAS or MEK plus PI3Kalpha triggers widespread apoptosis in NRAS-mutated RMS cells. Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kalpha-specific inhibitor BYL719 synergized to trigger apoptosis in NRAS-mutated RMS cells in vitro and in vivo. NRAS- or HRAS-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than RAS wild-type cell lines, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in NRAS-mutated than RAS wild-type RMS tumors in vivo.

Investigative Drug(s) 1 drug(s) in total

PD173074

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 4 (FGFR4) [4]

• Sensitive Disease: Alveolar rhabdomyosarcoma [ICD-11: 2B55.0]
• Molecule Alteration: Missense mutation; p.N535K (c.1605C>G)
• Sensitive Drug: PD173074
• Experimental Note: Identified from the Human Clinical Data

References

• Ref 1: Inhibition of Chemoresistance in Primary Tumor Cells by Camellia sinensis non fermentatum Extract Noviphenone (NPE ) .Anticancer Res. 2019 Aug;39(8):4101-4110. doi: 10.21873/anticanres.13568. 10.21873/anticanres.13568
• Ref 2: Response and mechanisms of resistance to larotrectinib and selitrectinib in metastatic undifferentiated sarcoma harboring oncogenic fusion of NTRK1 .JCO Precis Oncol. 2020;4:79-90. doi: 10.1200/po.19.00287. Epub 2020 Feb 14. 10.1200/po.19.00287
• Ref 3: NRAS-Mutated Rhabdomyosarcoma Cells Are Vulnerable to Mitochondrial Apoptosis Induced by Coinhibition of MEK and PI3KAlphaCancer Res. 2018 Apr 15;78(8):2000-2013. doi: 10.1158/0008-5472.CAN-17-1737. Epub 2018 Feb 6.
• Ref 4: Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534)PLoS One. 2013 Oct 4;8(10):e76551. doi: 10.1371/journal.pone.0076551. eCollection 2013.