Precision Targeting of Mutant PI3Kα in Cancer by Selective Degradation

Abstract

PIK3CA, which encodes the p110α catalytic subunit of PI3Kα, is one of the most frequently genetically activated kinases in solid tumors. In this issue of Cancer Discovery, Song and colleagues report that the related PI3Kα inhibitors taselisib and inavolisib trigger receptor tyrosine kinase (RTK)-dependent degradation of the mutant p110α protein in breast cancer cells that are positive for HER2 RTK, limiting feedback-mediated drug resistance and potentially widening the therapeutic index of PI3Kα inhibition.See related article by Song et al., p. 204.

Figure 1. Mutant specific targeting of p110α/p85β through inhibitor specific degradation

The PI3Kα complex is recruited to the plasma membrane by phosphorylated RTKs. Inhibition of PI3Kα by a non-mutant selective PI3K inhibitor (left panel) causes initial inhibition of PI3K pathway activity, however, feedback leads to increased RTK expression, which results in maintained PI3K signaling. For the p110α-mutant selective-degrading PI3K inhibitors inavolisib and taselisib (right panel), binding of the inhibitor to mutant p110α/p85β causes proteasome-mediated degradation downstream of activation by HER2/3. Degradation of p110α prevents feedback-mediated reactivation of the pathway, leading to sustained inhibition of mutant PI3K signalling. Shown is the binding of p85 to the HER2/HER3 RTK dimer, with the pYXXM motifs in HER3 functioning as docking sites for the SH2 domains of p85 (note that HER2 lacks such pYXXM motifs).