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 Journal of cellular and molecular medicine
Vol 17
Issue 11
Date 2013 Nov
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 Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
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 + 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
MPL W515L 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 MPL W515L in cell culture (PMID: 24251790). 24251790
JAK2 over exp MPL over exp Advanced Solid Tumor sensitive BEZ235 + Ruxolitinib Preclinical Actionable In a preclinical study, Jakafi (ruxolitinib) and BEZ235 synergistically inhibited growth of transformed cell lines over expressing wild-type Mpl and Jak2 in cell culture (PMID: 24251790). 24251790
JAK2 over exp MPL 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 Mpl and Jak2 in cell culture (PMID: 24251790). 24251790
MPL W515L Advanced Solid Tumor sensitive BEZ235 + Ruxolitinib Preclinical Actionable In a preclinical study, Jakafi (ruxolitinib) and BEZ235 synergistically inhibited growth of transformed cell lines over expressing MPL W515L 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 BEZ235 + 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 V617F MPL wild-type 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 Mpl and JAK2 V617F in cell culture (PMID: 24251790). 24251790
JAK2 V617F MPL wild-type 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 Mpl and JAK2 V617F 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
MPL W515L 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 MPL W515L in cell culture (PMID: 24251790). 24251790
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 MPL 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 Mpl and Jak2 in cell culture (PMID: 24251790). 24251790
JAK2 over exp Advanced Solid Tumor sensitive BEZ235 + 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 over exp MPL 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 Mpl and Jak2 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
MPL W515L 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 MPL W515L 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
JAK2 V617F MPL wild-type Advanced Solid Tumor sensitive BEZ235 + Ruxolitinib Preclinical Actionable In a preclinical study, Jakafi (ruxolitinib) and BEZ235 synergistically inhibited growth of transformed cell lines over expressing wild-type Mpl and JAK2 V617F in cell culture (PMID: 24251790). 24251790
JAK2 V617F MPL wild-type 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 Mpl and JAK2 V617F in cell culture (PMID: 24251790). 24251790