Reference Detail

Ref Type Journal Article
PMID (23670175)
Authors Bhagwat N, Levine RL, Koppikar P
Title Sensitivity and resistance of JAK2 inhibitors to myeloproliferative neoplasms.
Journal International journal of hematology
Vol 97
Issue 6
Date 2013 Jun
URL
Abstract Text The discovery of activating mutations in JAK2 and MPL in a majority of patients with myeloproliferative neoplasms (MPN) has led to the rapid clinical development of several JAK kinase inhibitors. Of these, the JAK1/2 inhibitor, ruxolitinib (INCB018424, Incyte Corporation) was recently approved for the treatment of patients with myelofibrosis (MF). JAK inhibitors have effectively reduced splenomegaly and high cytokine levels in patients leading to improvements in quality of life. However, they have not been successful in eliminating the mutant clone in a majority of patients. In vitro studies using saturation mutagenesis screens have revealed several mutations in JAK2 that confer resistance to JAK inhibitors. Nevertheless, these mutations have not been identified so far in JAK inhibitor-treated patients. A recent study from our laboratory demonstrated that chronic JAK kinase inhibition leads to JAK inhibitor persistence via transphosphorylation of JAK2 through other JAK kinase family members. This phenomenon is seen in cell lines, mouse models and patient samples. The JAK inhibitor persistent cells, however, still remain JAK2 dependent and therefore combination therapies that target JAK2 and other components of the JAK-STAT pathway along with JAK inhibitors may provide additional benefits and improve clinical outcomes in these patients.

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Molecular Profile Treatment Approach
JAK2 F694S JAK Inhibitor (Pan) - ATP competitive
JAK2 N622I JAK2 Inhibitor - ATP competitive
JAK2 I682D JAK Inhibitor (Pan)
JAK2 R683T JAK Inhibitor (Pan) - ATP competitive
JAK2 Y931F JAK Inhibitor (Pan) - ATP competitive
JAK2 T875N JAK Inhibitor (Pan) - ATP competitive
JAK2 L393V JAK2 Inhibitor
JAK2 F694S JAK2 Inhibitor
JAK2 V625F JAK2 Inhibitor - ATP competitive
JAK2 R867Q JAK2 Inhibitor
JAK2 I682D JAK Inhibitor (Pan) - ATP competitive
JAK2 T875N JAK2 Inhibitor
JAK2 R1063H JAK2 Inhibitor
JAK2 Y931F JAK2 Inhibitor - ATP competitive
JAK2 P58A JAK Inhibitor (Pan) - ATP competitive
JAK2 K539I JAK Inhibitor (Pan)
JAK2 D873N JAK2 Inhibitor
JAK2 V617F JAK2 Inhibitor
JAK2 Y317H JAK Inhibitor (Pan) - ATP competitive
JAK2 I682F JAK Inhibitor (Pan) - ATP competitive
JAK2 H538L JAK2 Inhibitor
JAK2 M483R JAK2 Inhibitor
JAK2 K539I JAK2 Inhibitor - ATP competitive
JAK2 I682S JAK Inhibitor (Pan)
JAK2 E864K JAK2 Inhibitor
JAK2 H574R JAK Inhibitor (Pan)
JAK2 L611S JAK Inhibitor (Pan) - ATP competitive
JAK2 K607E JAK2 Inhibitor
JAK2 H574R JAK2 Inhibitor - ATP competitive
JAK2 P933R JAK Inhibitor (Pan)
JAK2 H574R JAK Inhibitor (Pan) - ATP competitive
JAK2 Y44C JAK2 Inhibitor - ATP competitive
JAK2 H110R JAK Inhibitor (Pan) - ATP competitive
JAK2 R1063H JAK Inhibitor (Pan)
JAK2 R683S JAK2 Inhibitor
JAK2 I682S JAK Inhibitor (Pan) - ATP competitive
JAK2 E846D JAK Inhibitor (Pan)
JAK2 N542_E543del JAK2 Inhibitor - ATP competitive
JAK2 V881A JAK2 Inhibitor
JAK2 F556V JAK Inhibitor (Pan)
JAK2 F537_K539delinsL JAK Inhibitor (Pan)
JAK2 Y317H JAK2 Inhibitor - ATP competitive
JAK2 K607N JAK Inhibitor (Pan)
JAK2 C618R JAK Inhibitor (Pan)
JAK2 G417P JAK Inhibitor (Pan) - ATP competitive
JAK2 Y44C JAK Inhibitor (Pan)
JAK2 M483R JAK Inhibitor (Pan)
JAK2 K607E JAK Inhibitor (Pan) - ATP competitive
JAK2 I682F JAK Inhibitor (Pan)
JAK2 E846D JAK Inhibitor (Pan) - ATP competitive
JAK2 K607N JAK Inhibitor (Pan) - ATP competitive
JAK2 V366G JAK2 Inhibitor - ATP competitive
JAK2 R277K JAK Inhibitor (Pan) - ATP competitive
JAK2 F537_K539delinsL JAK Inhibitor (Pan) - ATP competitive
JAK2 R975G JAK Inhibitor (Pan)
JAK2 K539L JAK Inhibitor (Pan)
JAK2 R938Q JAK Inhibitor (Pan)
JAK2 R683E JAK Inhibitor (Pan) - ATP competitive
JAK2 Y44C JAK Inhibitor (Pan) - ATP competitive
JAK2 N542_E543del JAK2 Inhibitor
JAK2 T108A JAK Inhibitor (Pan) - ATP competitive
JAK2 R683S JAK Inhibitor (Pan)
JAK2 R564Q JAK Inhibitor (Pan) - ATP competitive
JAK2 N542_E543del JAK Inhibitor (Pan) - ATP competitive
JAK2 R683G JAK Inhibitor (Pan)
JAK2 act mut JAK2 Inhibitor
JAK2 N909K JAK2 Inhibitor
JAK2 Y317H JAK Inhibitor (Pan)
JAK2 N99S JAK2 Inhibitor
JAK2 R867Q JAK2 Inhibitor - ATP competitive
JAK2 L393V JAK2 Inhibitor - ATP competitive
JAK2 T108A JAK2 Inhibitor - ATP competitive
JAK2 L611S JAK2 Inhibitor
JAK2 G417P JAK Inhibitor (Pan)
JAK2 E846D JAK2 Inhibitor - ATP competitive
JAK2 R975G JAK2 Inhibitor
JAK2 T875N JAK Inhibitor (Pan)
JAK2 I682G JAK Inhibitor (Pan) - ATP competitive
JAK2 K539L JAK2 Inhibitor - ATP competitive
JAK2 R683G JAK2 Inhibitor - ATP competitive
JAK2 R683S JAK2 Inhibitor - ATP competitive
JAK2 R683T JAK2 Inhibitor
JAK2 E864K JAK Inhibitor (Pan)
JAK2 V366G JAK2 Inhibitor
JAK2 R683E JAK2 Inhibitor - ATP competitive
JAK2 P58A JAK2 Inhibitor
JAK2 R867Q JAK Inhibitor (Pan) - ATP competitive
JAK2 L611S JAK2 Inhibitor - ATP competitive
JAK2 N542_E543del JAK Inhibitor (Pan)
JAK2 Y317H JAK2 Inhibitor
JAK2 V881A JAK Inhibitor (Pan)
JAK2 D873N JAK Inhibitor (Pan) - ATP competitive
JAK2 I682F JAK2 Inhibitor
JAK2 R938Q JAK Inhibitor (Pan) - ATP competitive
JAK2 P58A JAK Inhibitor (Pan)
JAK2 H110R JAK2 Inhibitor - ATP competitive
JAK2 V366G JAK Inhibitor (Pan) - ATP competitive
JAK2 R277K JAK2 Inhibitor
JAK2 V366G JAK Inhibitor (Pan)
JAK2 H574R JAK2 Inhibitor
JAK2 V617F JAK2 Inhibitor - ATP competitive
JAK2 V617F JAK Inhibitor (Pan) - ATP competitive
JAK2 N99S JAK2 Inhibitor - ATP competitive
JAK2 P933R JAK Inhibitor (Pan) - ATP competitive
JAK2 V617I JAK Inhibitor (Pan) - ATP competitive
JAK2 V617I JAK2 Inhibitor - ATP competitive
JAK2 V625F JAK Inhibitor (Pan) - ATP competitive
JAK2 R564Q JAK2 Inhibitor - ATP competitive
JAK2 P933R JAK2 Inhibitor - ATP competitive
JAK2 T108A JAK Inhibitor (Pan)
JAK2 act mut JAK Inhibitor (Pan) - ATP competitive
JAK2 N99S JAK Inhibitor (Pan)
JAK2 R564Q JAK Inhibitor (Pan)
JAK2 G417P JAK2 Inhibitor - ATP competitive
JAK2 Y931C JAK2 Inhibitor
JAK2 I682S JAK2 Inhibitor
JAK2 F694L JAK Inhibitor (Pan) - ATP competitive
JAK2 T875N JAK2 Inhibitor - ATP competitive
JAK2 E846D JAK2 Inhibitor
JAK2 R683T JAK Inhibitor (Pan)
JAK2 H538L JAK Inhibitor (Pan)
JAK2 R683G JAK Inhibitor (Pan) - ATP competitive
JAK2 Y931C JAK Inhibitor (Pan)
JAK2 T108A JAK2 Inhibitor
JAK2 F694L JAK Inhibitor (Pan)
JAK2 L393V JAK Inhibitor (Pan)
JAK2 D873N JAK Inhibitor (Pan)
JAK2 M929I JAK Inhibitor (Pan)
JAK2 R683E JAK Inhibitor (Pan)
JAK2 I682G JAK2 Inhibitor
JAK2 P933R JAK2 Inhibitor
JAK2 F694L JAK2 Inhibitor - ATP competitive
JAK2 F556V JAK2 Inhibitor - ATP competitive
JAK2 M483R JAK2 Inhibitor - ATP competitive
JAK2 V617I JAK2 Inhibitor
JAK2 I682S JAK2 Inhibitor - ATP competitive
JAK2 H538L JAK Inhibitor (Pan) - ATP competitive
JAK2 F537_K539delinsL JAK2 Inhibitor - ATP competitive
JAK2 D873N JAK2 Inhibitor - ATP competitive
JAK2 R683T JAK2 Inhibitor - ATP competitive
JAK2 N99S JAK Inhibitor (Pan) - ATP competitive
JAK2 H538_K539delinsQL JAK2 Inhibitor - ATP competitive
JAK2 I682G JAK2 Inhibitor - ATP competitive
JAK2 R683E JAK2 Inhibitor
JAK2 C618R JAK Inhibitor (Pan) - ATP competitive
JAK2 V625F JAK2 Inhibitor
JAK2 I682G JAK Inhibitor (Pan)
JAK2 R564Q JAK2 Inhibitor
JAK2 C618R JAK2 Inhibitor
JAK2 H538_K539delinsQL JAK2 Inhibitor
JAK2 H110R JAK2 Inhibitor
JAK2 R938Q JAK2 Inhibitor - ATP competitive
JAK2 L393V JAK Inhibitor (Pan) - ATP competitive
JAK2 V617F JAK Inhibitor (Pan)
JAK2 I682D JAK2 Inhibitor
JAK2 Y931F JAK2 Inhibitor
JAK2 G935R JAK Inhibitor (Pan)
JAK2 K539I JAK2 Inhibitor
JAK2 V625F JAK Inhibitor (Pan)
JAK2 P58A JAK2 Inhibitor - ATP competitive
JAK2 I682D JAK2 Inhibitor - ATP competitive
JAK2 N909K JAK Inhibitor (Pan)
JAK2 Y931F JAK Inhibitor (Pan)
JAK2 R867Q JAK Inhibitor (Pan)
JAK2 N622I JAK2 Inhibitor
JAK2 F694S JAK Inhibitor (Pan)
JAK2 R1063H JAK2 Inhibitor - ATP competitive
JAK2 K607N JAK2 Inhibitor
JAK2 H538_K539delinsQL JAK Inhibitor (Pan)
JAK2 Y44C JAK2 Inhibitor
JAK2 act mut JAK2 Inhibitor - ATP competitive
JAK2 H110R JAK Inhibitor (Pan)
JAK2 G417P JAK2 Inhibitor
JAK2 F556V JAK Inhibitor (Pan) - ATP competitive
JAK2 R277K JAK Inhibitor (Pan)
JAK2 L611S JAK Inhibitor (Pan)
JAK2 M483R JAK Inhibitor (Pan) - ATP competitive
JAK2 K607E JAK Inhibitor (Pan)
JAK2 K539I JAK Inhibitor (Pan) - ATP competitive
JAK2 F694L JAK2 Inhibitor
JAK2 R1063H JAK Inhibitor (Pan) - ATP competitive
JAK2 F537_K539delinsL JAK2 Inhibitor
JAK2 F694S JAK2 Inhibitor - ATP competitive
JAK2 K607E JAK2 Inhibitor - ATP competitive
JAK2 N622I JAK Inhibitor (Pan)
JAK2 C618R JAK2 Inhibitor - ATP competitive
JAK2 N622I JAK Inhibitor (Pan) - ATP competitive
JAK2 I682F JAK2 Inhibitor - ATP competitive
JAK2 act mut JAK Inhibitor (Pan)
JAK2 K539L JAK2 Inhibitor
JAK2 V617I JAK Inhibitor (Pan)
JAK2 K539L JAK Inhibitor (Pan) - ATP competitive
JAK2 F556V JAK2 Inhibitor
JAK2 H538L JAK2 Inhibitor - ATP competitive
JAK2 R683G JAK2 Inhibitor
JAK2 R683S JAK Inhibitor (Pan) - ATP competitive
JAK2 G935R JAK2 Inhibitor
JAK2 R938Q JAK2 Inhibitor
JAK2 M929I JAK2 Inhibitor
JAK2 R277K JAK2 Inhibitor - ATP competitive
JAK2 H538_K539delinsQL JAK Inhibitor (Pan) - ATP competitive
JAK2 K607N JAK2 Inhibitor - ATP competitive
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
Variant Impact Protein Effect Variant Description Associated with drug Resistance
P1057S missense unknown JAK2 P1057S lies within the protein kinase domain 2 of the Jak2 protein (UniProt.org). P1057S has been demonstrated to occur as a secondary drug resistance mutation (PMID: 23670175), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Apr 2019). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References