Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is commonly deregulated in cancer. In recent years, the results of the first phase I clinical trials with PI3K inhibitors have become available. In comparison to other targeted agents such v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors in melanoma or crizotinib in anaplastic lymphoma receptor tyrosine kinase (ALK) translocated tumors, the number of objective responses to PI3K inhibitors is less dramatic. In this review we propose possible strategies to optimize the clinical development of PI3K inhibitors: by exploring the potential role of PI3K isoform-specific inhibitors in improving the therapeutic index, molecular characterization as a basis for patient selection, and the relevance of performing serial tumor biopsies to understand the associated mechanisms of drug resistance. The main focus of this review will be on PI3K isoform-specific inhibitors by describing the functions of different PI3K isoforms, the preclinical activity of selective PI3K isoform-specific inhibitors and the early clinical data of these compounds.

Figure 1

Phosphatidylinositol 3-kinase (PI3K) pathway activation. Tyrosine kinase receptors (TKR) can interact with several PI3K isoforms. RAS proteins can activate PI3Kα and γ isoforms. In addition certain RAS proteins can activate PI3Kδ isoform. G protein-coupled receptors (GPCR) preferentially interact with the PI3Kβ or γ isoforms. Once activated by any of these mechanisms, PI3K interacts with the lipid membrane phosphorylating phosphatidylinositol 4,5-bisphosphate (PIP2) generating phosphatidylinositol 3,4,5-trisphosphate (PIP3). PTEN (phosphatase and tensin homologue deleted on chromosome 10) converts PIP3 into PIP2, regulating the final amount of PIP3 generated. PIP3 triggers a signaling cascade through the activation of AKT, phosphoinositide-dependent protein kinase 1 (PDK1) and their downstream effectors. G = G protein G; p110 = PI3K catalytic subunit; p85 = class IA PI3K regulatory subunit; p87 = class IB PI3K regulatory subunit; p101 = class IB regulatory subunit.