The present and future of PI3K inhibitors for cancer therapy

Abstract

Phosphoinositide-3- kinase (PI3K) signaling regulates cellular proliferation, survival and metabolism, and its aberrant activation is one of the most frequent oncogenic events across human cancers. In the last few decades, research focused on the development of PI3K inhibitors, from preclinical tool compounds to the highly specific medicines approved to treat patients with cancer. Herein we discuss current paradigms for PI3K inhibitors in cancer therapy, focusing on clinical data and mechanisms of action. We also discuss current limitations in the use of PI3K inhibitors including toxicities and mechanisms of resistance, with specific emphasis on approaches aimed to improve their efficacy.

Figure 1.. The PI3K-AKT pathway and the most common PIK3CA mutations in cancer.

a. The gene expression profile of PI3K isoforms in normal human tissues shown in log2 (TPM+1) scale based on http://gepia.cancer-pku.cn (visited on April 2021). b. Receptor tyrosine kinase (RTK) activation by insulin or growth factors mediates tyrosine phosphorylation which allows the recruitment of the lipid kinase PI3K to the plasma membrane through the p85 regulatory subunit. PI3K phosphorylates the lipid phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). The lipid phosphatase PTEN dephosphorylates PIP3 back to PIP2. PIP3 recruits the serine/threonine kinase AKT to the plasma membrane, where it gets phosphorylated and activated through phosphorylation at T308 by the PDK1 kinase and S473 by mTORC2 kinase complex. AKT then phosphorylates a numerous of substrates promoting glucose, metabolism, cell cycle arrest, cell growth, proliferation, and translation. P denotes protein phosphorylation events. c. The most frequent mutations of the PI3KCA gene by MSK-IMPACT. d. The percentages of the alteration frequency of the PIK3CA gene across human cancers by MSK-IMPACT. Amino-terminal adaptor-binding domain (ABD); Ras-binding domain (RBD); Protein-kinase-C homology-2 (C2).

Figure 2.. The non-cell autonomous and the cell-autonomous effects of PI3K inhibitors.

PI3K inhibitors have well-studied cell-autonomous effects in cancer cells that lead to a cytostatic and cytotoxic response. These include the activation of intrinsic apoptosis, the reduction of glucose metabolism, translation inhibition, and changes in transcriptional regulation through the FOXO transcription factors among others. However, in addition to these effects, PI3K inhibitors can also exert non-cell autonomous affects in the organism and tumor microenvironment that can significantly contribute to the antitumoral effect. For example, administration of PI3K inhibitors lead to short and long-term metabolic responses that affect tumor nutrient availability and glycemic and insulinemic response. These compounds also have remarkable anti-angiogenic properties that are mediated by the alpha isoform. Inhibitors that target the delta and gamma isoform of PI3K inhibitors have been shown to affect macrophage activation (including polarization and phagocytosis), inhibition of regulatory T-cells, and inhibition of suppressive myeloid cells and neutrophils. Most of these changes result in activation of cytotoxic T-cells that promote cancer cell killing. The predominant PI3K isoform mediating each of these cellular effects have been highlighted in red (alpha), green (delta), and blue (gamma).

Figure 3.. Proposed approaches to increase the therapeutic index of PI3K inhibitors.

Several factors that may increase the therapeutic index of PI3K inhibitors are required to improve the clinical application of these agents. These include pharmacological strategies, such as careful consideration of dose and schedule; patient stratification allowing the identification of biomarkers and mediators of drug resistance; the effect of metabolism and diet, and the successful management of common toxicities such as hyperglycemia, GI problems, and rash among others. Similar to many other therapies, there are novel modalities to inhibit PI3K that need to be considered, which should overcome the current limitations of PI3K inhibitors in the clinic.