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

SIMPLE SUMMARY: The PI3K/AKT pathway is one of the most important signaling nodes in cancer. While class I PI3K roles in cancer are well known, class II and III functions in physiology and physiopathology are poorly studied. Moreover, the interactions between pathways controlled by all three classes are not fully understood. The understanding of the mechanisms behind their cooperative functions could be key for efficient PI3K combination targeting in cancer therapy. This review will focus on the recent advances on the roles of the different classes of PI3K in cancer biology, their cross-regulations and their targeting in preclinical models. 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.