Co-occurring PIK3CA mutations in cis increase PI3K/AKT/mTOR signaling pathway activation and sensitivity to PI3Kα inhibitors in breast cancer


PI3K/AKT/mTOR signaling plays an important role in breast cancer. The prevalence of PIK3CA mutation in HR-positive/Her2-negative breast cancer is around 40%. Interestingly, in patients with PIK3CA mutation,10-15% patients harbor multiple–PIK3CA-mutant, and most of them have double mutations. The scientists from Memorial Sloan Kettering Cancer Center demonstrated that co-occurring PIK3CA mutations in cis could increase PI3K/AKT/mTOR signaling pathway activation and enhance proliferation. The mechanism is caused by decreasing the inhibitory protein p85α binding affinity with p110α, and increasing the membrane binding ability of p110α. The activating PI3K/AKT/mTOR signaling can be inhibited by PI3Kα inhibitor, aplelisib or GDC-0077. Finally, a retrospective analysis of a phase III study (SANDPIPER) showed that co-occurring PIK3CA mutations were associated with significant clinical benefits in breast cancer patients who received PI3Kα inhibitor (taselisib) treatment. These results indicated that breast cancer patients with co-occurring PIK3CA mutations in cis may get additional benefit from PI3Kα inhibitors.

Vasan N, et al. Science. 2019