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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.
Highlights
Phosphatidylinositol 3-kinases (PI3Ks) represent a family of lipid kinases that plays a key role in signal transduction, cell metabolism and survival [1,2]
The amount of phosphatidylinositol 3 (PIP3) generated and resultant PI3K pathway activation are tightly regulated by the tumor suppressor protein, phosphatase and tensin homologue deleted on chromosome 10 (PTEN)
Are alternate pathway activation and tumor heterogeneity the reasons why PI3K inhibitors are not declared as panacea based on the currently available clinical data? Is the pathway so critical in the human organism that compensatory feedback mechanisms emerge very quickly upon inhibition? Are existent PI3K inhibitors in clinical development potent enough with optimal pharmacokinetic and pharmacodynamic properties? Would the early phase clinical results have been superior if all patients had been preselected according to molecular characteristics? As knowledge accumulates in the PI3K pathway and more potent PI3K inhibitors become available, rational application of these agents as monotherapy or in combination is within reach
Summary
Phosphatidylinositol 3-kinases (PI3Ks) represent a family of lipid kinases that plays a key role in signal transduction, cell metabolism and survival [1,2]. PI3Ka-specific inhibitors In addition to its effects on cell growth, proliferation and survival, class IA PI3K regulates glucose metabolism through insulin signaling [31,32,33] It is commonly deregulated in cancer through mutations or amplifications of the PIK3CA gene or through alterations in the function of upstream tumor suppressors such as PTEN (Table 1). This population was selected based on the higher antitumor activity observed in preclinical models with PIK3CA mutations or amplifications using the Cancer Cell Line Encyclopedia [42] This was the first reported study of a PI3K inhibitor in which molecular prescreening was undertaken starting from the dose escalation part.
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