Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	77	20	2017 10 15	5554-5563	Cancer Res

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
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
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