The Role of Avapritinib for the Treatment of Systemic Mastocytosis

Sumbly, Vikram; Landry, Ian; Iqbal, Saba; Bhatti, Zamaraq; Alshamam, Mohsen; Ashfaq, Salman; Rizzo, Vincent

doi:10.7759/cureus.18385

Cited by 3 publications

(2 citation statements)

References 50 publications

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“…However, only a few study data are available, and not all patients with AdvSM may respond to this kinase inhibitor. However, these studies support the efficacy of kinase inhibitors in the treatment of these malignant conditions [7]. The characterization and dissection of cooperating pathogenetic pathways may set the basis for the development of novel therapeutic strategies useful for this critical subset of patients.…”

Section: Introductionmentioning

confidence: 89%

Combined Inhibition of Polo-Like Kinase-1 and Wee1 as a New Therapeutic Strategy to Induce Apoptotic Cell Death in Neoplastic Mast Cells

Mancini

Monaldi

Santis

et al. 2022

Cancers

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Systemic mastocytosis (SM) is due to the pathologic accumulation of neoplastic mast cells in one or more extracutaneous organ(s). Although midostaurin, a multikinase inhibitor active against both wild-type and D816V-mutated KIT, improves organ damage and symptoms, a proportion of patients relapse or have resistant disease. It is well known that Aurora kinase A (AKA) over-expression promotes tumorigenesis, but its role in the pathogenesis of systemic mastocytosis (SM) has not yet been investigated. Evidence from the literature suggests that AKA may confer cancer cell chemo-resistance, inhibit p53, and enhance Polo-like kinase 1 (Plk1), CDK1, and cyclin B1 to promote cell cycle progression. In this study, we aimed to investigate the pathogenetic role of AKA and Plk1 in the advanced forms of SM. We demonstrate here, for the first time, that SM cell lines display hyper-phosphorylated AKA and Plk1. Danusertib (Aurora kinase inhibitor) and volasertib (Plk1 inhibitor) inhibited growth and induced apoptotic cell death in HMC-1.1 and -1.2 cells. Their growth-inhibitory effects were associated with cell cycle arrest and the activation of apoptosis. Cell cycle arrest was associated with increased levels of phospho-Wee1. Wee1 inhibition by MK1775 after 24 h treatment with danusertib or volasertib, when cells were arrested in G2 phase and Wee1, was overexpressed and hyper-activated, resulting in a significantly higher rate of apoptosis than that obtained from concomitant treatment with danusertib or volasertib + MK1775 for 48 h. In conclusion, Plk1 and AKA, alone or together with Wee1, are attractive therapeutic targets in neoplastic MCs. Repurposing Plk1 or AKA ± Wee1 inhibitors in advanced clinical development for other indications is a therapeutic strategy worthy of being explored, in order to improve the outcome of patients with advanced SM.

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Section: Introductionmentioning

confidence: 89%

Combined Inhibition of Polo-Like Kinase-1 and Wee1 as a New Therapeutic Strategy to Induce Apoptotic Cell Death in Neoplastic Mast Cells

Mancini

Monaldi

Santis

et al. 2022

Cancers

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“…Imatinib, an inhibitor of wild-type KIT, PDGFR, and BCR-ABL, is currently FDA approved for systemic mastocytosis patients who lack a KIT D816V mutation or whose KIT mutation is unclear [13]. In contrast, apravitinib is FDA approved for the treatment of systemic mastocytosis in adult patients with the specific KIT D816V mutation [14].…”

Section: B a Cmentioning

confidence: 99%

A widespread blistering eruption: diffuse cutaneous mastocytosis

Ewulu,

Cardis,

Carter

et al. 2024

DOJ

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Avapritinib Carries the Risk of Drug Interaction via Inhibition of UDP-Glucuronyltransferase (UGT) 1A1

Lv,

Wang,

Wang

et al. 2024

CDM

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Background: Avapritinib is the only drug for adult patients with PDGFRA exon 18 mutated unresectable or metastatic Gastrointestinal Stromal Tumor (GIST). Although avapritinib has been approved by the FDA for three years, little is known about the risk of Drug-drug Interac-tions (DDIs) via UDP-glucuronyltransferases (UGTs) inhibition. Objective: The aim of the present study was to systematically evaluate the inhibitory effects of avapritinib against UGTs and to quantitatively estimate its potential DDIs risk in vivo. Methods: Recombinant human UGTs were employed to catalyze the glucuronidation of sub-strates in a range of concentrations of avapritinib. The kinetics analysis was performed to evaluate the inhibition types of avapritinib against UGTs. The quantitative prediction of DDIs was done using In vitro-in vivo Extrapolation (IVIVE). Results: Avapritinib had a potent competitive inhibitory effect on UGT1A1. Quantitative predic-tion results showed that avapritinib administered at clinical doses might result in a 14.85% in-crease in the Area Under the Curve (AUC) of drugs primarily cleared by UGT1A1. Moreover, the Rgut value was calculated to be 18.44. result: Avapritinib exhibited a potently competitive inhibition against UGT1A1 with a Ki, u value of 3.46 ± 0.30 μM. Quantitative prediction of DDI risk model indicated that avapritinib administered at 300 mg/day might result in a 14.85% area increase in under the plasma concentration-time curve (AUC) of drugs mainly metabolizing by UGT1A1, implying low risk of interaction via liver metabolism in liver; and Rgut value of 697.02 was much higher than 11 in UGT1A1, indicating a high risk of DDI in intestine. Conclusion: Avapritinib has the potential to cause intestinal DDIs via the inhibition of UGT1A1. Additional attention should be paid when avapritinib is coadministered with UGT1A1 substrates. other: no

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The Role of Avapritinib for the Treatment of Systemic Mastocytosis

Cited by 3 publications

References 50 publications

Combined Inhibition of Polo-Like Kinase-1 and Wee1 as a New Therapeutic Strategy to Induce Apoptotic Cell Death in Neoplastic Mast Cells

Combined Inhibition of Polo-Like Kinase-1 and Wee1 as a New Therapeutic Strategy to Induce Apoptotic Cell Death in Neoplastic Mast Cells

A widespread blistering eruption: diffuse cutaneous mastocytosis

Avapritinib Carries the Risk of Drug Interaction via Inhibition of UDP-Glucuronyltransferase (UGT) 1A1

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