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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. | ||||||||||||
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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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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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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 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 | 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 | 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 | 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 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 |