Reference Detail

Ref Type

Journal Article

PMID

(24251790)

Authors

Choong ML, Pecquet C, Pendharkar V, Diaconu CC, Yong JW, Tai SJ, Wang SF, Defour JP, Sangthongpitag K, Villeval JL, Vainchenker W, Constantinescu SN, Lee MA

Title

Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of cellular and molecular medicine	17	11	2013 Nov	1397-409	J Cell Mol Med

URL

Abstract Text

Current JAK2 inhibitors used for myeloproliferative neoplasms (MPN) treatment are not specific enough to selectively suppress aberrant JAK2 signalling and preserve physiological JAK2 signalling. We tested whether combining a JAK2 inhibitor with a series of serine threonine kinase inhibitors, targeting nine signalling pathways and already used in clinical trials, synergized in inhibiting growth of haematopoietic cells expressing mutant and wild-type forms of JAK2 (V617F) or thrombopoietin receptor (W515L). Out of 15 kinase inhibitors, the ZSTK474 phosphatydylinositol-3'-kinase (PI3K) inhibitor molecule showed strong synergic inhibition by Chou and Talalay analysis with JAK2 and JAK2/JAK1 inhibitors. Other pan-class I, but not gamma or delta specific PI3K inhibitors, also synergized with JAK2 inhibitors. Synergy was not observed in Bcr-Abl transformed cells. The best JAK2/JAK1 and PI3K inhibitor combination pair (ruxolitinib and GDC0941) reduces spleen weight in nude mice inoculated with Ba/F3 cells expressing TpoR and JAK2 V617F. It also exerted strong inhibitory effects on erythropoietin-independent erythroid colonies from MPN patients and JAK2 V617F knock-in mice, where at certain doses, a preferential inhibition of JAK2 V617F mutated progenitors was detected. Our data support the use of a combination of JAK2 and pan-class I PI3K inhibitors in the treatment of MPNs.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
JAK2 over exp	Advanced Solid Tumor	sensitive	Ruxolitinib + TGX-221	Preclinical	Actionable	In a preclinical study, Jakafi (ruxolitinib) and TGX-221 synergistically inhibited growth of transformed cell lines over expressing wild-type Jak2 in cell culture (PMID: 24251790).	24251790
JAK2 over exp	Advanced Solid Tumor	sensitive	Dactolisib + Ruxolitinib	Preclinical	Actionable	In a preclinical study, Jakafi (ruxolitinib) and BEZ235 synergistically inhibited growth of transformed cell lines over expressing wild-type Jak2 in cell culture (PMID: 24251790).	24251790
JAK2 V617F	Advanced Solid Tumor	sensitive	Ruxolitinib + TGX-221	Preclinical	Actionable	In a preclinical study, Jakafi (ruxolitinib) and TGX-221 synergistically inhibited growth of transformed cell lines over expressing JAK2 V617F in cell culture (PMID: 24251790).	24251790
JAK2 V617F	Advanced Solid Tumor	sensitive	Ruxolitinib + ZSTK474	Preclinical	Actionable	In a preclinical study, Jakafi (ruxolitinib) and ZSTK474 synergistically inhibited growth of transformed cell lines over expressing JAK2 V617F in cell culture (PMID: 24251790).	24251790
JAK2 V617F	Advanced Solid Tumor	sensitive	Dactolisib + Ruxolitinib	Preclinical	Actionable	In a preclinical study, Jakafi (ruxolitinib) and BEZ235 synergistically inhibited growth of transformed cell lines over expressing JAK2 V617F in cell culture (PMID: 24251790).	24251790
JAK2 over exp	Advanced Solid Tumor	sensitive	Pictilisib + Ruxolitinib	Preclinical	Actionable	In a preclinical study, Jakafi (ruxolitinib) and Pictilisib (GDC-0941) synergistically inhibited growth of transformed cell lines over expressing wild-type Jak2 in cell culture (PMID: 24251790).	24251790
JAK2 over exp	Advanced Solid Tumor	sensitive	Ruxolitinib + ZSTK474	Preclinical	Actionable	In a preclinical study, Jakafi (ruxolitinib) and ZSTK474 synergistically inhibited growth of transformed cell lines over expressing wild-type Jak2 in cell culture (PMID: 24251790).	24251790
JAK2 V617F	Advanced Solid Tumor	sensitive	Pictilisib + Ruxolitinib	Preclinical	Actionable	In a preclinical study, Jakafi (ruxolitinib) and Pictilisib (GDC-0941) synergistically inhibited growth of transformed cell lines over expressing JAK2 V617F in cell culture (PMID: 24251790).	24251790