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|Ref Type||Journal Article|
|Authors||Bruner JK, Ma HS, Li L, Qin ACR, Rudek MA, Jones RJ, Levis MJ, Pratz KW, Pratilas CA, Small D|
|Title||Adaptation to TKI Treatment Reactivates ERK Signaling in Tyrosine Kinase-Driven Leukemias and Other Malignancies.|
|Date||2017 10 15|
|Abstract Text||FMS-like tyrosine kinase-3 (FLT3) tyrosine kinase inhibitors (TKI) have been tested extensively to limited benefit in acute myeloid leukemia (AML). We hypothesized that FLT3/internal tandem duplication (ITD) leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are associated with an incomplete response. Here, we identified reactivation of ERK signaling within hours following treatment of FLT3/ITD AML cells with selective inhibitors of FLT3. When these cells were treated with inhibitors of both FLT3 and MEK in combination, ERK reactivation was abrogated and anti-leukemia effects were more pronounced compared with either drug alone. ERK reactivation was also observed following inhibition of other tyrosine kinase-driven cancer cells, including EGFR-mutant lung cancer, HER2-amplified breast cancer, and BCR-ABL leukemia. These studies reveal an adaptive feedback mechanism in tyrosine kinase-driven cancers associated with reactivation of ERK signaling in response to targeted inhibition. Cancer Res; 77(20); 5554-63. ©2017 AACR.|
|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|
|NRAS Q61L||acute myeloid leukemia||predicted - sensitive||PD-0325901||Preclinical - Cell culture||Actionable||In a preclinical study, PD-0325901 treatment induced apoptosis and inhibited proliferation of an acute myeloid leukemia cell line harboring NRAS Q61L in culture (PMID: 28923853).||28923853|
|FLT3 exon 14 ins||acute myeloid leukemia||sensitive||Sorafenib + Trametinib||Preclinical - Cell culture||Actionable||In a preclinical study, Nexavar (sorafenib) combined with Mekinist (trametinib) enhanced apoptosis in acute myeloid leukemia cell lines harboring FLT3 internal tandem duplication (ITD) mutations in culture (PMID: 28923853).||28923853|
|NRAS Q61L||acute myeloid leukemia||no benefit||PD-0325901 + Sorafenib||Preclinical - Cell culture||Actionable||In a preclinical study, addition of Nexavar (sorafenib) to PD-0325901 treatment did not demonstrate increased sensitivity compared to PD-0325901 alone in an acute myeloid leukemia cell line harboring NRAS Q61L in culture (PMID: 28923853).||28923853|
|FLT3 exon 14 ins||acute myeloid leukemia||sensitive||PD-0325901 + Sorafenib||Preclinical - Patient cell culture||Actionable||In a preclinical study, Nexavar (sorafenib) and PD-0325901 synergistically induced apoptosis and inhibited proliferation of acute myeloid leukemia (AML) cell lines harboring FLT3 internal tandem duplication (ITD) mutations in culture, inhibited Erk phosphorylation in FLT3-ITD mutant AML patient cells, and reduced leukemic burden in a FLT3-ITD mutant AML cell line xenograft model (PMID: 28923853).||28923853|