Pharmacodynamic Biomarker Development for PI3K Pathway Therapeutics

Abstract

AbstrAct:The phosphatidylinositol 3-kinase (PI3K) signaling pathway is integral to many essential cell processes, including cell growth, differentiation, proliferation, motility, and metabolism. Somatic mutations and genetic amplifications that result in activation of the pathway are frequently detected in cancer. This has led to the development of rationally designed therapeutics targeting key members of the pathway. Critical to the successful development of these drugs are pharmacodynamic biomarkers that aim to define the degree of target and pathway inhibition. In this review, we discuss the pharmacodynamic biomarkers that have been utilized in early-phase clinical trials of PI3K pathway inhibitors. We focus on the challenges related to development and interpretation of these assays, their optimal integration with pharmacokinetic and predictive biomarkers, and future strategies to ensure successful development of PI3K pathway inhibitors within a personalized medicine paradigm for cancer.

Novel DNA targeted therapies for head and neck cancers: clinical potential and biomarkers

“…However, PI3K inhibition alone can trigger compensatory feedback via the RAS/MEK/ERK pathway or EGFR which induces resistance. Combination therapy with other therapeutic agents or DNA damaging agents can achieve synergistic effects [ 54 , 61 , 62 ]. RT activates EGFR and other prosurvival pathways like PI3K.…”

“…To assess the level of inhibition of the PI3K pathway, the phosphorylation level of AKT or its downstream effectors gives a good indication [ 61 , 79 ]. The phosphorylation status of AKT was significantly associated with the sensitivity for the dual PI3K-mTOR inhibitor PF-05212384 in HNSCC cells and can predict resistance to standard HNSCC therapies like Cetuximab and RT, regardless the PIK3CA status.…”

“…Even better, this resistance can be overcome by combination of mTOR-PI3K and MEK inhibition therapy [ 57 ]. The major drawbacks to use AKT phosphorylation level as biomarker are the strict handling and sampling conditions of the tissue, which makes implementation in clinical trials difficult [ 59 , 61 ].…”

“…Finally, a recent study concluded that 15% of the mutations in PI3K pathway genes are subclonal rather than truncal. These subclonal driver mutations can explain the uncertain predictive value of PI3K/AKT/mTOR mutations and suggest that the response to PI3K inhibitors should be assessed by the proportion of tumor cells in which the driver mutation is identified [ 61 ].…”

Excessive Reactive Oxygen Species and Exotic DNA Lesions as an Exploitable Liability

“…42 Once oxidized, PTEN is inactive, and the AKT pathway is activated. 43 This highlights a general scheme in which phosphatases are oxidatively inactivated to move the balance of signaling toward kinase action. The problematic side quickly starts to arise.…”