The cell biology behind the oncogenic PIP3 lipids

Abstract

The different mechanisms of phosphoinositide 3-kinase (PI3K) activation in cancer as well as the events that result in PI3K pathway reactivation after patient treatment with PI3K inhibitors was discussed on October 15-17th, 2018, in the medieval town of Baeza (Universidad Internacional de Andalucía, Spain) at the workshop entitled 'The cell biology behind the oncogenic PIP3 lipids'. These topics and the data presented regarding cellular functions altered by PI3K deregulation, the cooperation of PI3K/PTEN mutations with other tumor drivers, and the lessons learned for PI3K-targeted therapy, are discussed below.

Fig. 1.

Novel findings in the oncogenic PI3K/AKT pathway. The figure highlights that, apart from receptor RTK activation, association with GPCRs also affects activation of PI3K (note PI3K is shown in the figure as a complex of its subunits p85 and p110), particularly in the case of PI3Kβ. The composition of the p85–p110 complex changes in some tumor types as they progress, with the p85α regulatory isoform being frequently downregulated, and/or the p85β being overexpressed; this switch in p85 subunit usage contributes to tumor progression. Activation of AKT involves the action of protein kinase D1 (Pdk1) and the TORC2 complex downstream of PI3K. In addition to the well-known substrates [FOXO transcription factors and TSC2 (a regulator of the TORC1 complex)], TRF1, a component of the shelterin complex, which protects telomere integrity in chromosomes, is also a substrate of AKT; PI3K/AKT inhibition impairs telomere integrity. Another well-known substrate of AKT, Mdm2, is a negative regulator of p53. Nuclear p53 can be stabilized by direct binding to poly-phosphoinositides. Following sustained AKT inhibition (i.e. in cancer treatment), SGK3, a kinase similar to AKT, might acquire the capacity of phosphorylating AKT substrates, thereby triggering resistance to AKT inhibitory compounds. Along the same lines, in some tumor types that overexpress TRIB2, despite inhibition of PI3K or mTOR (the core kinase of TORC1 complexes), AKT can remain active owing to the interaction with TRIB2. (For simplicity, a fragment of single lipid bilayer is represented to separate the cytosol and the nucleus).