Drug Information

Drug (ID: DG01683) and It's Reported Resistant Information

• Name: Alpelisib/Binimetinib
• Synonyms: Alpelisib/Binimetinib
• Target: .; NOUNIPROTAC; [1]

Type(s) of Resistant Mechanism of This Drug

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Acute myeloid leukemia [ICD-11: 2A60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [2]

• Molecule Alteration: Missense mutation; p.G12D (c.35G>A)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NOMO1 cells; Bone marrow; Homo sapiens (Human); CVCL_1609
• In Vitro Model: BaF3 cells; Bone; Mus musculus (Mouse); CVCL_0161
• In Vitro Model: THP1 cell; Peripheral blood; Homo sapiens (Human); CVCL_0006
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay

Rhabdomyosarcoma [ICD-11: 2B55]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [1]

• Molecule Alteration: Missense mutation; p.Q61H (c.183A>T)
• Sensitive Disease: Alveolar rhabdomyosarcoma [ICD-11: 2B55.0]
• 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.

References

• Ref 1: 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 2: Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110AlphaJ Clin Invest. 2014 Apr;124(4):1794-809. doi: 10.1172/JCI69927. Epub 2014 Feb 24.