Abstract
Despite the development of novel treatments in the past 15 years, many blood cancers still remain ultimately fatal and difficult to treat, particularly acute myeloid leukaemia (AML) and multiple myeloma (MM). While significant progress has been made characterising small-scale genetic mutations and larger-scale chromosomal translocations that contribute to the development of various blood cancers, less is understood about the complex microenvironment of the bone marrow (BM), which is known to be a key player in the pathogenesis of chronic lymphocytic leukaemia (CLL), AML and MM. This niche acts as a sanctuary for the cancerous cells, protecting them from chemotherapeutics and encouraging clonal cell survival. It does this by upregulating a plethora of signalling cascades within the malignant cell, with the phosphatidylinositol-3-kinase (PI3K) pathway taking a critical role. This review will focus on how the PI3K pathway influences disease progression and the individualised role of the PI3K subunits. We will also summarise the current clinical trials for PI3K inhibitors and how these trials impact the treatment of blood cancers.
Highlights
The phosphatidylinositol-3-kinase (PI3K) pathway has been shown to be constitutively active in the majority of multiple myeloma (MM) and acute myeloid leukaemia (AML) cells [1,2,3] and is critical for the tumour cell growth and survival [4,5,6]
Many reviews have highlighted the importance of PI3K in chronic lymphocytic leukaemia (CLL), this review aims to describe the known individualised roles of the p110 PI3K regulatory subunits in the context of MM and AML
The PI3K pathway has been shown to be activated via a wide assortment of receptor tyrosine kinases (RTKs)—including platelet-derived growth factor receptor (PDGFR) [51,52], c-MET [53], insulin-like growth factor-I receptor (IGF-IR) [54] and Fms-Related Tyrosine Kinase 3 (FLT3) [55]
Summary
The phosphatidylinositol-3-kinase (PI3K) pathway has been shown to be constitutively active in the majority of multiple myeloma (MM) and acute myeloid leukaemia (AML) cells [1,2,3] and is critical for the tumour cell growth and survival [4,5,6]. P110δ has a critical role in B-Cell development and has been shown to have an oncogenic role in a number of blood cancers, including CLL, acute lymphoblastic leukaemia (ALL), MM and AML [6,46,47] This has led to the development of p110δ-specific inhibitors, discussed below, that have been shown to slow and reduce tumour growth, even in the presence of protective bone marrow microenvironment (BMM) signalling. Mutation of the PI3KCG gene has previously been implicated in lung cancer [49] and inhibition of the p110γ subunit resulted in reduced proliferation of these cells in idiopathic pulmonary fibrosis [50] Considering this isoform’s prominent role in macrophage motility, this may provide a therapeutic target in AML
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