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.

Biomedical Research Center University Hospital Hradec Kralove Hradec Kralove Czech Republic

College of Life Science Yangtze University Jingzhou China

College of Physical Education and Health Chongqing College of International Business and Economics Chongqing China

Department of Chemistry and Biochemistry Mendel University in Brno Brno Czech Republic

Department of Chemistry Faculty of Science University of Hradec Kralove Czech Republic

Faculty of Chemical and Food Technology Slovak University of Technology in Bratislava Bratislava Slovakia

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