PI3Kβ inhibition: all that glitters is not gold

PI3K/Akt in platelet integrin signaling and implications in thrombosis

“…This is actually in line with previous observations ex vivo (Martin et al, 2010). Since integrity of thrombi and its resistance to increased shear forces are dependent on the strength of plateleteplatelet interaction maintained by integrin bonds, it has been considered that this role of PI3Kb is a direct consequence of its central contribution to integrin outside-in signaling (Torti, 2015).…”

In-depth PtdIns(3,4,5)P3 signalosome analysis identifies DAPP1 as a negative regulator of GPVI-driven platelet function

“…Indeed, it has allowed us to identify DAPP1 as a new PI3K-regulated player in GPVI-mediated platelet activation and an important negative regulator of collagen-mediated thrombus formation. Furthermore, given the challenges and limitations of directly targeting the proximal, ubiquitous, and multifunctional class I PI3Ks for therapeutic means,13,14 the characterization of downstream effectors may provide novel targets100 for the regulation of specific aspects of platelet signaling and function.…”

“…Furthermore, AZD6482, a selective PI3Kβ inhibitor, has demonstrated promising antiplatelet effects and tolerance in humans 11,12. Thus, PI3Kβ inhibition appears to afford protection from occlusive arterial thrombosis while demonstrating limited bleeding risk,6,8,9,12 although the potential for embolization with this strategy needs additional investigation 13,14…”

PI3K inhibitors in thrombosis and cardiovascular disease

“…Despite this promise for PI3Kβ as an anti‐thrombotic target, its clinical potential may be hampered by the observation that its inhibition may lead to increased risk of embolism of thrombotic material [75,164]. Laurent et al [75] demonstrated a key role for PI3Kβ, via a AKT‐GSK3 axis, in thrombus stability and recruitment of new platelets to the growing thrombus at high shear rate, observed using mice with selective loss of PI3Kβ in the megakaryocyte lineage and human platelets treated with AZD6482.…”

“…Laurent et al [75] demonstrated a key role for PI3Kβ, via a AKT‐GSK3 axis, in thrombus stability and recruitment of new platelets to the growing thrombus at high shear rate, observed using mice with selective loss of PI3Kβ in the megakaryocyte lineage and human platelets treated with AZD6482. The thrombus instability with loss of PI3Kβ activity at high shear rate was associated with the formation of platelet emboli from large thrombi, suggesting the potential for secondary ischaemic events, with the growing thrombus itself likely contributing to the elevation of local shear in the blood vessel [75,164]. Further studies are needed to determine whether this property would rule out PI3Kβ inhibitors for clinical use, particularly since P 2 Y 12 inhibition may cause a similar effect which has not limited its use clinically [156], and tailoring of PI3Kβ inhibitor dosage may mean a suitable level of inhibition can be found [164].…”