PIK3CA hotspot mutation is well established as an oncogenic driver event in cancer and its durable and efficacious inhibition is a focus in the development and testing of clinical cancer therapeutics. However, hundreds of cancer-associated PIK3CA mutations remain uncharacterized, their sensitivity to PI3K inhibitors unknown. Here, we describe a series of PIK3CA C-terminal mutations, primarily nucleotide insertions, that produce a frame-shifted protein product with an extended C terminus. We report that these mutations occur at a low frequency across multiple cancer subtypes, including breast, and are sufficient to drive oncogenic transformation in vitro and in vivo. We demonstrate that the oncogenicity of these mutant p110α proteins is dependent on p85 but not Ras association. P110α-selective pharmacologic inhibition blocks transformation in cells and mammary tumors characterized by PIK3CA C-terminal mutation. Taken together, these results suggest patients with breast and other tumors characterized by PIK3CA C-terminal frameshift mutations may derive benefit from p110α-selective inhibitors, including the recently FDA-approved alpelisib.

PIK3CA热点突变已被广泛确立为癌症的致癌驱动因素，其持久而有效的抑制作用是临床癌症治疗剂开发和测试的重点。然而，数百个与癌症相关的PIK3CA突变仍未鉴定，其对PI3K抑制剂的敏感性尚不清楚。在这里，我们描述了一系列的PIK3CAC端突变，主要是核苷酸插入，产生带有扩展C端的移码蛋白质产物。我们报道，这些突变在包括乳腺癌在内的多种癌症亚型中以较低的频率发生，并且足以在体外和体内驱动致癌性转化。我们证明这些突变的p110α蛋白的致癌性取决于p85，而不是Ras协会。P110α选择性药理抑制作用可阻止以PIK3CA C端突变为特征的细胞和乳腺肿瘤中的转化。综上所述，这些结果表明患有以PIK3CA C端移码突变为特征的乳腺和其他肿瘤患者可能会受益于p110α-选择性抑制剂，包括最近获得FDA批准的alpelisib。