LAUSR

PIK3CA is one of the most frequently mutated oncogene in cancer. Phosphoinositide 3-kinase (PI3K) is a heterodimer comprising two subunits: a catalytic subunit (p110) and a regulatory subunit (p85). Activating mutations in PIK3CA are found inw30%-40% of patients with breast cancer (BC) and induce hyperactivation of the catalytic subunit. This mutation has been associated with endocrine therapy resistance in luminal BC, and also with anti-HER2 therapy in HER2þ BC. In May 2019, alpelisib, an a-specific PI3K inhibitor, was approved for the treatment of patients with advanced PIK3CA-mutant luminal BC. However, the efficacy has been modest, in part due to a limited therapeutic index. Song et al. published in Cancer Discovery an impressive article showing a unique mechanism of action of PI3K inhibitors. The authors demonstrated that taselisib and inavolisib were stronger inducers of cell antiproliferation in PIK3CA-mutant cancer cells than other inhibitors. Furthermore, inavolisib in combination with endocrine treatment plus CDK4/6 inhibitors showed efficacy and tolerability in preclinical PIK3CA-mutant luminal BC models. To explain this differential efficacy in PIK3CA mutant models between different PI3K inhibitors, they described a novel mechanism. Taselisib and inavolisib depleted the mutant p110a protein. The molecular process underlying this degradation was through ubiquitination. Thereby, mutant p110a oncoprotein was less stable and more vulnerable to inhibitor-mediated degradation in a ubiquitinand proteasome-dependent manner. Interestingly, they showed that receptor tyrosine kinase (RTK) activity plays a key role in regulating p110a degradation by recruiting p110a to the membrane through p85b (an isoform of p85 regulatory subunit) for ubiquitination. In fact, low RTK activity resulted in inefficient mutant p110a degradation, suggesting that the degrader mechanism of action may not provide additional benefit over drugs with a nondegrader mechanism in HER2-negative mutant cells. To complete the analysis, they explored the activity of inavolisib in HER2-amplified BC. In these tumors, HER2-targeted therapy is the standard of care. However, patients with PIK3CA mutations are less responsive to anti-HER2 therapies. As they expected, degrader inhibitors in combination with trastuzumab plus pertuzumab or T-DM1 showed better response in in vitro and in vivo models. Overall, this work reveals a new mechanism of action to exploit in PIK3CAmutant tumors, and opens an exciting path to pushing PI3Ka degraders in patients with HER2-positive BC.