Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

Pillinger, Genevra; Abdul‐Aziz, Amina; Zaitseva, Lyubov; Lawes, Matthew; MacEwan, David J.; Bowles, Kristian M.; Rushworth, Stuart A.

doi:10.1038/srep12949

Cited by 31 publications

(34 citation statements)

References 49 publications

(65 reference statements)

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“…28,[50][51][52][53][54][55][56] It inhibited the migration of both pre-BCR (CLL) 28,55 and proposed as a mechanism involved in redistribution of leukemia cells from tissues into the blood. 40,57 Using CRISPR-Cas9-mediated genome editing, we demonstrated that BTK KO could not fully recapitulate the effects of ibrutinib on pre-BCR 1 RCH-ACV cells.…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK

Kim

Hurtz

Koehrer

et al. 2017

Blood

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Section: Discussionmentioning

confidence: 99%

Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK

Kim

Hurtz

Koehrer

et al. 2017

Blood

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“…Independent research has demonstrated a sensitivity for ibrutinib in FLT3-mutated cells and a potential benefit for FLT3-mutated AML patients. 9,13,15 In our analysis, we identified 3 patients with FLT3-mutated AML. Response in this small group did not show promising results, with all 3 patients experiencing disease progression within the first 2 months of treatment.…”

Section: Discussionmentioning

confidence: 99%

“…8 Additional preclinical studies demonstrated activity of ibrutinib in subsets of AML, including CD117-expressing AML 12 and AML with internal tandem duplication of the juxtamembrane region of the FMS-like tyrosine kinase 3 receptor (FLT3-ITD). 13 The objectives of this study were to evaluate the efficacy, safety, and tolerability of single-agent ibrutinib or ibrutinib in combination with either cytarabine or azacitidine in the treatment of patients with AML. It was hypothesized that ibrutinib would improve treatment outcomes in patients with AML, with adequate tolerability.…”

Section: Introductionmentioning

confidence: 99%

Clinical Experience With Ibrutinib Alone or in Combination With Either Cytarabine or Azacitidine in Patients With Acute Myeloid Leukemia

Cortes

Jonas

Graef

et al. 2019

Clinical Lymphoma Myeloma and Leukemia

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Preclinical studies have suggested that ibrutinib may have a clinical benefit in acute myeloid leukemia (AML). Treatment with ibrutinib alone or in combination with cytarabine or azacitidine was evaluated in 36 patients with AML. The study was terminated because of limited efficacy. Safety was consistent with established safety profiles of the individual drugs. The potential utility of ibrutinib in AML remains uncertain. Background: Preclinical studies have suggested a role for Bruton tyrosine kinase (BTK) as a potential therapeutic target in acute myeloid leukemia (AML), and anti-AML activity in vivo has been demonstrated with BTK inhibitors. Patients and Methods: In this open-label phase 2a study, patients with AML were treated with ibrutinib 560 mg per day alone (cohort 1; n ¼ 7), or ibrutinib in combination with either cytarabine 20 mg administered subcutaneously twice daily for 10 days of a 28-day cycle (cohort 2; n ¼ 21) or azacitidine 75 mg/m 2 administered intravenously once daily on days 1 to 7 of a 28-day cycle (cohort 3; n ¼ 8). Best overall response (primary end point), overall survival, and safety were summarized. Results: A total of 36 patients were enrolled and received treatment; median duration of ibrutinib treatment was 5.4 weeks, and median time on study was 16 months. Of 24 patients evaluable for response, 1 partial remission (cohort 3) and 1 complete remission (cohort 2) were observed; the remaining responses were treatment failures. Median overall survival was 4.0 months in cohort 1, 2.2 months in cohort 2, 2.8 months in cohort 3, and 2.4 months for the overall population. No unexpected safety signals were identified. Grade 3 or higher adverse events that occurred in ! 10% of patients included AML progression, febrile neutropenia, pneumonia, anemia, thrombocytopenia, fatigue, asthenia, and respiratory failure. Conclusion: Ibrutinib alone or in combination with cytarabine or azacitidine demonstrated an acceptable safety profile. However, limited efficacy with ibrutinib was observed in patients with AML.

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“…This implies that the SYK downmodulation in the ITD cell lines is the result of abrogating FLT3-ITD-dependent SYK activation as previously suggested by Puissant et al [30], whereas inhibition of SYK signaling can occur directly in the FLT3 WT OCI-AML3 cell line. Several reports have shed light on the involvement of BTK in AML, especially in the context of FLT3-ITD mutation [32,33,[42][43][44], and ARQ 531 potently inhibits BTK in the AML cell lines independent of FLT3 status (Fig. 3d).…”

Section: Arq 531 Modulates Alterative Oncogenic Kinasesmentioning

confidence: 95%

“…Most importantly, targeting SFK disrupts SYK phosphorylation [29], which is upregulated in FLT3-ITD patients and transactivates FLT3 [30,31]. Finally, several studies have shown the importance of BTK in FLT3 AML pathogenesis [32,33]. Together, these studies suggest that the use of a multi-kinase inhibitor targeting SFK and BTK could achieve clinical benefit by targeting upstream regulators of FLT3 similar to the use of dual FLT3/SYK inhibitors in AML [31,34,35].…”

Section: Introductionmentioning

confidence: 94%

Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia

et al. 2020

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Background: Acute myeloid leukemia (AML) is the most common type of adult leukemia. Several studies have demonstrated that oncogenesis in AML is enhanced by kinase signaling pathways such as Src family kinases (SFK) including Src and Lyn, spleen tyrosine kinase (SYK), and bruton's tyrosine kinase (BTK). Recently, the multi-kinase inhibitor ArQule 531 (ARQ 531) has demonstrated potent inhibition of SFK and BTK that translated to improved preclinical in vivo activity as compared with the irreversible BTK inhibitor ibrutinib in chronic lymphocytic leukemia (CLL) models. Given the superior activity of ARQ 531 in CLL, and recognition that this molecule has a broad kinase inhibition profile, we pursued its application in pre-clinical models of AML. Methods: The potency of ARQ 531 was examined in vitro using FLT3 wild type and mutated (ITD) AML cell lines and primary samples. The modulation of pro-survival kinases following ARQ 531 treatment was determined using AML cell lines. The effect of SYK expression on ARQ 531 potency was evaluated using a SYK overexpressing cell line (Ba/F3 murine cells) constitutively expressing FLT3-ITD. Finally, the in vivo activity of ARQ 531 was evaluated using MOLM-13 disseminated xenograft model. Results: Our data demonstrate that ARQ 531 treatment has anti-proliferative activity in vitro and impairs colony formation in AML cell lines and primary AML cells independent of the presence of a FLT3 ITD mutation. We demonstrate decreased phosphorylation of oncogenic kinases targeted by ARQ 531, including SFK (Tyr416), BTK, and fms-related tyrosine kinase 3 (FLT3), ultimately leading to changes in downstream targets including SYK, STAT5a, and ERK1/2. Based upon in vitro drug synergy data, we examined ARQ 531 in the MOLM-13 AML xenograft model alone and in combination with venetoclax. Despite ARQ 531 having a less favorable pharmacokinetics profile in rodents, we demonstrate modest single agent in vivo activity and synergy with venetoclax. Conclusions: Our data support consideration of the application of ARQ 531 in combination trials for AML targeting higher drug concentrations in vivo.

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Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

Cited by 31 publications

References 49 publications

Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK

Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK

Clinical Experience With Ibrutinib Alone or in Combination With Either Cytarabine or Azacitidine in Patients With Acute Myeloid Leukemia

Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia

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