Targeting Class I-II-III PI3Ks in Cancer Therapy: Recent Advances in Tumor Biology and Preclinical Research

Abstract

Phosphatidylinositol-3-kinase (PI3K) enzymes, producing signaling phosphoinositides at plasma and intracellular membranes, are key in intracellular signaling and vesicular trafficking pathways. PI3K is a family of eight enzymes divided into three classes with various functions in physiology and largely deregulated in cancer. Here, we will review the recent evidence obtained during the last 5 years on the roles of PI3K class I, II and III isoforms in tumor biology and on the anti-tumoral action of PI3K inhibitors in preclinical cancer models. The dependency of tumors to PI3K isoforms is dictated by both genetics and context (e.g., the microenvironment). The understanding of class II/III isoforms in cancer development and progression remains scarce. Nonetheless, the limited available data are consistent and reveal that there is an interdependency between the pathways controlled by all PI3K class members in their role to promote cancer cell proliferation, survival, growth, migration and metabolism. It is unknown whether this feature contributes to partial treatment failure with isoform-selective PI3K inhibitors. Hence, a better understanding of class II/III functions to efficiently inhibit their positive and negative interactions with class I PI3Ks is needed. This research will provide the proof-of-concept to develop combination treatment strategies targeting several PI3K isoforms simultaneously.

Phosphatidylinositol 4-kinase III alpha governs cytoskeletal organization for invasiveness of liver cancer cells

“…Potential roles of PIK3C2γ in cancer are particularly ill-defined. While some studies in murine pancreatic cancer models even regarded it as a tumor suppressor [33,34], mutations in PIK3C2G were associated with poor prognosis in intrahepatic cholangiocarcinoma [35]. Our data now provide a first hint towards a contribution of PIK3C2γ to invasiveness of HCC.…”

Discoidin domain receptor 2 signaling through PIK3C2α in fibroblasts promotes lung fibrosis

“…We found that PIK3C2α, one of three class II PI3 kinases, is a critical regulator of fibroblast activation in response to TGFβ (Figure 3) and survival against inducers of apoptosis (Figure 2). There is a growing understanding that there is a complex signaling network among the PI3 kinases and crosstalk with other signaling molecules including receptor tyrosine kinases and serine/threonine kinases [22,25,59]. In some cases, deletion or inhibition of one PI3 kinase may be compensated by increased activity of other PI3 kinases.…”

“…PI3 kinase signaling regulates cell proliferation, survival, activation, and migration. There are emerging data that complex crosstalk takes place among the PI3 kinase family members [22]. The signaling pathways regulated by PI3 kinases can tightly regulate signaling through other PI3 kinases.…”

Molecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers

“…The PI3K signaling pathway is a complex series of events initiated at the cellular membrane level, involving tightly regulated mechanisms and involves PI3K, AKT, and mTOR substrates. PI3Ks are divided into three different classes (I-II-II) depending on their structural and specific features [10]. Class I PI3Ks are again subclassified into class IA (PI3Kα, PI3Kβ, and PI3Kδ) and class IB (PI3Kγ) encoded by PIK3CA, PIK3CB, PIK3CD and PIK3CG genes, respectively, consisting of a catalytic p110 subunits (p110α, p110β, p110δ, or p110γ) and a regulatory subunit [11,12].…”