Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK)

Abstract

Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus. Notably, most of the PIKK inhibitors (such as VX-970 and M3814) related to DNA damage response have also shown good efficacy in clinical trials. However, these drugs still require a suitable combination therapy to overcome drug resistance or improve antitumor activity. Based on the aforementioned facts, we summarised the efficacy of PIKK, PI3K, and AKT inhibitors in the therapy of human malignancies and the resistance mechanisms of targeted therapy, in order to provide deeper insights into cancer treatment.

Keywords:

• PI3K
• PIKK
• AKT
• inhibitors
• anticancer therapy

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (Grant no. 31972741); the Czech Health Research Council (project no. NU20-03–00477), by MH CZ – DRO (UHHK, project no. 00179906), by the InoMed project (reg. no. CZ.02.1.01/0.0/0.0/18_069/0010046) co-funded by the European Union, and the Excelence project PrF UHK (2216/2023–2024) Czech Republic.