The emerging role of PI3K inhibitors for solid tumour treatment and beyond

Phosphoinositide 3-kinases (PI3Ks) play a central role in tumourigenesis with recurrent activating mutations of its p110 alpha subunit (PIK3CA) identified in several tumours. Although several PI3K inhibitors are approved for haematological malignancies, only alpelisib was approved in solid tumours and for the treatment of PIK3CA-related overgrowth spectrum (PROS) syndrome. Traditional PI3K inhibitors inhibit both wild-type and mutant PI3K with almost equal potency, thus limiting their efficacy due to on-target toxicity. Since the initiation of phase I clinical trials investigating next generation allosteric mutant and isoform selective PIK3CA inhibitors, there has been a surge in interest in PIK3CA targeting in solid tumours. Preclinical characterisation of these compounds showed that maximal mutant protein inhibition fails to elicit metabolic and glucose homoeostasis dysregulation, one of the dose limiting toxicities of both selective and pan PI3K inhibitors. While extreme selectivity can be hypothesised to grant activity and safety advantage to these novel agents, on the other hand reduced benefit can be speculated for patients harbouring multiple or rare PIK3CA mutations. This review summarises the current understanding of PI3K alterations and the state-of-the-art treatment strategies in PI3K driven solid tumours, while also exploring the potential intrinsic and acquired resistance mechanisms to these agents, and the emerging role of mutant selective PIK3CA inhibitors.

Automated summary

Phosphoinositide 3-kinases (PI3Ks) play a crucial role in tumorigenesis, particularly the p110 alpha subunit (PIK3CA) with activating mutations found in various tumors. Current PI3K inhibitors have limited efficacy due to on-target toxicity, inhibiting both wild-type and mutant PI3Ks. However, the development of mutant and isoform selective PIK3CA inhibitors has surged interest in targeting PIK3CA in solid tumors. This review summarizes the understanding of PI3K alterations, treatment strategies, and emerging resistance mechanisms and the role of mutant selective PIK3CA inhibitors.