ARQ531: the therapy that targets multiple pathways in acute myeloid leukemia.

So far this century we have witnessed the introduction of a number of targeted therapies, developed through rational drug design, which have changed cancer treatment and resulted in improved outcomes for many patients, including those with a spectrum of chronic lymphoid and myeloid malignancies.[1,2] However, despite improved understanding of the biology of acute myeloid leukemia (AML), similar scale benefits by targeting kinases and other intracellular and surface proteins have yet to be realized, and the prognosis for patients with AML remains poor. Moreover, cytotoxic drugs and therapies developed in the last century currently remain the backbone of AML treatment, and as AML primarily affects the elderly, many of whom are therefore frail with multiple co-morbidities, the clinical application of such curative therapies is somewhat limited.[3] Furthermore, even in those fit enough for intensive chemotherapy, both relapse and treatment resistance are common, due to the aggressive nature of the disease. The search therefore continues for biology-driven targeted treatments for patients with AML which can be delivered to all, and at the same time increase remission rates, reduce relapses and prevent treatment resistance. The expectation is that these therapies will come from advances in the understanding of the biology of AML.

Tyrosine kinases are known to play a role in the tumorigenesis of both solid tumors and hematological malignancies and they therefore present a potential treatment target.[4] In particular, Bruton tyrosine kinase (BTK) inhibitors have been shown to be effective in the treatment of a number of hematologic malignancies including chronic lymphocytic leukemia and lymphomas.[5-7] BTK is a non-receptor tyrosine kinase with an important role in both normal and malignant hematopoiesis.[8] Its expression and phosphorylation are high in AML and BTK inhibition with ibrutinib has been shown to have an anti-leukemic effect.[9] Moreover, many other tyrosine kinases have been shown to be activated in AML and hematologic malignancies including SYK, FLT3, MAPK, PI3K and AKT.[10,11] This knowledge supports further exploration of tyrosine kinase inibitors in the treatment of AML.

In this issue of Haematologica, Soncini et al. explore the potential role of ARQ531, a reversible small molecule inhibitor of BTK and a number of other kinases, in the management of AML[12] (Figure 1). BTK was shown to be constitutively active in a range of different subtypes of AML, suggesting that targeting it could have a broad clinical application in all patients with AML. ARQ531 was observed to have dose-dependent anti-leukemic activity by inducing apoptosis in both AML cell lines and primary AML cells.

Figure 1.

Schematic representation of the mechanism of action of ARQ531 in acute myeloid leukemia. BTK: Bruton tyrosine kinase; ERK: extracellular-signal-related kinase; MAPK: mitogen-activated protein kinase; AML: acute myeloid leukemia.

The effect of ARQ531 was superior to that of treatment with ibrutinib and this was likely due to the broader mode of action of ARQ531. While ARQ531 has anti-BTK activity its action does not appear to be dependent on BTK and it was shown to inhibit a number of other oncogenic pathways as well. Thus, ARQ531 treatment reduced cell viability even after knock-down of BTK in AML cells.

We know that AML is heavily reliant on its tumor microenvironment[13] and disrupting this relationship is a crucial step in improving AML treatments and therefore outcomes for patients. When considering effectiveness of new treatments, we must therefore assess whether they are able to target leukemic cells within this supportive environment. Soncini et al. were able to demonstrate that the antileukemic activity of ARQ531 was preserved when AML cells were co-cultured with mesenchymal stromal cells. Moreover, the viability of the mesenchymal stromal cells as well as that of other non-malignant cells, including hematopoietic stem cells, was not affected by treatment with ARQ531. This is important when considering the potential toxicity of a drug as there is a need to protect nonmalignant cells in order to prevent side effects and reduce treatment-related morbidity and mortality.

A number of oncogenic pathways have been shown to drive leukemogenisis, disease progression and treatment resistance. In addition to upregulation of BTK, these include activation of the mitogen-activated protein kinase (MAPK) pathway and dysregulation of the hematopoietic transcriptional factor MYB, which have been implicated in the pathogensis of AML.[14,15] The mode of action of ARQ531 is complex and genetic analysis revealed that it inhibits a number of different oncogenic pathways in AML. The data published in this issue show that ARQ531 disrupts the oncogenic MAPK pathway by inhibiting ERK and AKT activation as well as downregulating MYC. Furthermore, ARQ531 was shown to deregulate and promote degradation of the oncogenic driver MYB. Interestingly the action on all of these pathways, including BTK, MAPK and MYB, as well, potentially, as others not yet identified, appears to have a cumulative effect on cell viability. Inhibition of each pathway individually is less effective in reducing cell viability than using ARQ531, suggesting that additional pathways are important in this drug’s mode of action. It is clear that leukemogenesis relies on the dysregulation of multiple oncogenic pathways and therefore targeting only one of these is not sufficient to achieve cell death and reduce tumor growth. A drug that has the ability to target a number of these pathways does, therefore, have greater potential to effectively eliminate malignant cells and at the same time has little or no lasting effect on non-malignant cells.

To demonstrate this Soncini et al. designed an in vivo experiment using a patient-derived AML mouse model. Following engraftment of immunocompromised mice with primary AML cells they demonstrated that treatment with ARQ531 impaired AML engraftment, reduced tumor burden and improved the animals’ survival. Furthermore, there were no signs of toxicity, suggesting that ARQ531 could be an effective and well-tolerated treatment for AML in the future. However, a note of caution is that many potential therapies have been shown to have in vivo efficacy in AML, but when tested clinically have had little or no effect on this disease.

In conclusion, by targeting a number of different oncogenic pathways, in vitro and in vivo treatment with ARQ531 results in reduced AML cell viability, reduced tumor growth and improved survival of animals. The research by Soncini et al. suggests that a multi-targeted inhibitor such as ARQ531 is required to impair AML survival effectively; since this drug does not rely specifically on high expression of BTK or other tyrosine kinases it could be widely applicable to different subtypes of AML.