Early phase development of PI3kinase inhibitors for anticancer therapies

Introduction: The PI3K/Akt/mTOR pathway plays a crucial role in regulating cell proliferation, survival and metabolism. Its aberrant activation promotes tumor development and progression. The most common oncogenic feature is represented by genetic alterations of PI3KCA that encodes the catalytic subunit p110α. In fact, several studies have highlighted the prevalence of somatic point mutations and/or amplification of PI3KCA in many neoplastic forms, making it a promising therapeutic target. In recent years, some PI3KCA inhibitors have been approved, others are under clinical development. Areas covered: In this review, we summarize the current knowledge on the PI3K/Akt/mTOR pathway with a focus on PI3KCA genetic alterations in tumor development. Furthermore, we discuss the emerging role of PI3KCA inhibitors (approved and under investigation) as a therapeutic strategy in different tumor types including their current limitations. Expert opinion: PI3KCA-specific inhibitors represent a new class of promising drugs in the treatment of tumors with the mutated P110α subunit. However, despite the proven improvement in clinical outcomes, the management of patients in terms of efficacy and toxicity remains the main challenge. To maximize efficacy and safety, molecular stratification of patients by genomic profiling and the development of targeted combinations are crucial to optimizing benefits.