PIK3CA 突变发生在约 8% 的癌症中，包括约 40% 的 HR 阳性乳腺癌，其中 PI3K-α (PI3Ka) 选择性抑制剂 alpelisib 已获得 FDA 批准与氟维司群联合使用。尽管之前的研究已经确定了耐药机制，例如 PTEN 丢失，但对 PI3Ka 抑制剂的临床获得性耐药仍知之甚少。通过对 39 名对 PI3Ka 抑制剂产生耐药性的晚期乳腺癌患者进行连续液体活检和快速尸检，我们观察到 50% 的患者在 PI3K 通路内发生基因组改变，包括 PTEN 丢失和激活 AKT1 突变。值得注意的是，虽然先前报道二次 PIK3CA 突变会增加对 PI3Ka 抑制剂的敏感性，但我们发现 PIK3CA 中出现的二次耐药突变会改变抑制剂结合袋。一些突变对 PI3Ka 选择性抑制剂与泛 PI3K 抑制剂具有不同的影响，但新型变构泛突变选择性 PI3Ka 抑制剂 RLY-2608 可以克服所有突变诱导的耐药性。总之，这些发现为指导克服 PIK3CA 突变癌症耐药性的策略提供了见解。

PIK3CA mutations occur in ~8% of cancers, including ~40% of HR-positive breast cancers, where the PI3K-alpha (PI3Ka)-selective inhibitor alpelisib is FDA-approved in combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as PTEN loss, clinical acquired resistance to PI3Ka inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies in 39 patients with advanced breast cancer developing acquired resistance to PI3Ka-inhibitors, we observe that 50% of patients acquire genomic alterations within the PI3K-pathway, including PTEN loss and activating AKT1 mutations. Notably, while secondary PIK3CA mutations were previously reported to increase sensitivity to PI3Ka-inhibitors, we identified emergent secondary resistance mutations in PIK3CA that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Ka-selective vs. pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Ka-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers.