Drug Information

Drug (ID: DG01676) and It's Reported Resistant Information

Name	BEZ235/Ruxolitinib
Synonyms	BEZ235/Ruxolitinib Click to Show/Hide

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

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Solid tumour/cancer [ICD-11: 2A00-2F9Z]

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Thrombopoietin receptor (TPOR)				[1]
Sensitive Disease	Solid tumour/cancer [ICD-11: 2A00-2F9Z]			Disease Info
Molecule Alteration	Missense mutation		p.W515L (c.1544G>T)	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	Ba/F3 cells	Colon	Homo sapiens (Human)	CVCL_0161
In Vivo Model	JAK2 mutant Ba/F3 tumour mouse model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CellTiter-Glo assay; Colony assay

Colorectal cancer [ICD-11: 2B91]

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: AKT serine/threonine kinase (AKT)				[2]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Phosphorylation		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	PI3K-Akt signaling pathway		Activation	hsa04151
In Vitro Model	BRAF L525R cells	N.A.	Homo sapiens (Human)	N.A.
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in?BRAF?L525R cells but not in?BRAF?V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in?BRAF?L525R cells but not in?BRAF?V600E cells or selumetinib-resistant?BRAF?L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance.

References

Ref 1	Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitorsJ Cell Mol Med. 2013 Nov;17(11):1397-409. doi: 10.1111/jcmm.12156. Epub 2013 Nov 19.
Ref 2	Regulation of MEK inhibitor selumetinib sensitivity by AKT phosphorylation in the novel BRAF L525R mutant. Int J Clin Oncol. 2023 May;28(5):654-663.