Combination Therapies with Kinase Inhibitors for Acute Myeloid Leukemia Treatment

Abstract

Targeting kinase activity is considered to be an attractive therapeutic strategy to overcome acute myeloid leukemia (AML) since aberrant activation of the kinase pathway plays a pivotal role in leukemogenesis through abnormal cell proliferation and differentiation block. Although clinical trials for kinase modulators as single agents remain scarce, combination therapies are an area of therapeutic interest. In this review, the author summarizes attractive kinase pathways for therapeutic targets and the combination strategies for these pathways. Specifically, the review focuses on combination therapies targeting the FLT3 pathways, as well as PI3K/AKT/mTOR, CDK and CHK1 pathways. From a literature review, combination therapies with the kinase inhibitors appear more promising than monotherapies with individual agents. Therefore, the development of efficient combination therapies with kinase inhibitors may result in effective therapeutic strategies for AML.

Identification of triciribine as a novel myeloid cell differentiation inducer

“…The PI3K/Akt-mammalian target of rapamycin (mTOR) pathway is one of the intracellular pathways aberrantly upregulated in cancers including hematopoietic malignancies [17]. Recently, it was reported that targeting the PI3K/Akt/mTOR signaling pathway had some benefit, even in clinical settings [18][19][20][21]. The PI3K/Akt axis is aberrantly activated in T-cell acute lymphoblastic leukemia (T-ALL).…”

Transcriptional Response to Standard AML Drugs Identifies Synergistic Combinations

“…MEK inhibitors are also being explored in various clinical trials as standalone agents (clinical trial NCT02089230) and combinations (clinical trialös NCT02105350 and NCT02041481). Clinically, MEK inhibitors are considered non-effective as a standalone agent [ 38 , 39 , 40 ]. This is consistent with our observation that MEK inhibitor PD98059 is not cytotoxic alone, even at high dosages.…”