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Ref Type Journal Article
PMID (28923853)
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.
Journal Cancer research
Vol 77
Issue 20
Date 2017 10 15
URL
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.

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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
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