Department of Liver Surgery, Center of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
Cell Death Dis. 2021 Oct 8;12(10):920. doi: 10.1038/s41419-021-04206-5.
Hepatocellular carcinoma (HCC) is the sixth most common primary cancer with an unsatisfactory long-term survival. Gain of function mutations of PIK3CA occur in a subset of human HCC. Alpelisib, a selective PIK3CA inhibitor, has been approved by the FDA to treat PIK3CA mutant breast cancers. In this manuscript, we evaluated the therapeutic efficacy of alpelisib, either alone or in combination, for the treatment of HCC. We tested alpelisib in mouse HCC induced by hydrodynamic injection of c-Met/PIK3CA(H1047R) (c-Met/H1047R), c-Met/PIK3CA(E545K) (c-Met/E545K), and c-Met/sgPten gene combinations. Alpelisib slowed down the growth of c-Met/H1047R and c-Met/E545K HCC but was ineffective in c-Met/sgPten HCC. Mechanistically, alpelisib inhibited p-ERK and p-AKT in c-Met/H1047R and c-Met/E545K HCC progression but did not affect the mTOR pathway or genes involved in cell proliferation. In human HCC cell lines transfected with PIK3CA(H1047R), alpelisib synergized with the mTOR inhibitor MLN0128 or the CDK4/6 inhibitor palbociclib to suppress HCC cell growth. In c-Met/H1047R mice, alpelisib/MLN0128 or alpelisib/palbociclib combination therapy caused tumor regression. Our study demonstrates that alpelisib is effective for treating PIK3CA-mutated HCC by inhibiting MAPK and AKT cascades. Furthermore, combining alpelisib with mTOR or CDK4/6 inhibitors has a synergistic efficacy against PIK3CA-mutated HCC, providing novel opportunities for precision medicine against HCC.
肝细胞癌（HCC）是第六种最常见的原发性癌症，其长期生存状况不佳。PIK3CA 的功能获得性突变发生在人类 HCC 的一部分中。Alpelisib 是一种选择性 PIK3CA 抑制剂，已被 FDA 批准用于治疗 PIK3CA 突变型乳腺癌。在本手稿中，我们评估了 alpelisib 单独或联合治疗 HCC 的治疗效果。我们在由 c-Met/PIK3CA（H1047R）（c-Met/H1047R）、c-Met/PIK3CA（E545K）（c-Met/E545K）和 c-Met/sgPten 基因组合水力注射诱导的小鼠 HCC 中测试了 alpelisib。Alpelisib 减缓了 c-Met/H1047R 和 c-Met/E545K HCC 的生长，但对 c-Met/sgPten HCC 无效。从机制上讲，alpelisib 抑制了 c-Met/H1047R 和 c-Met/E545K HCC 进展中的 p-ERK 和 p-AKT，但不影响 mTOR 途径或参与细胞增殖的基因。在转染了 PIK3CA（H1047R）的人 HCC 细胞系中，alpelisib 与 mTOR 抑制剂 MLN0128 或 CDK4/6 抑制剂 palbociclib 协同作用，抑制 HCC 细胞生长。在 c-Met/H1047R 小鼠中，alpelisib/MLN0128 或 alpelisib/palbociclib 联合治疗导致肿瘤消退。我们的研究表明，alpelisib 通过抑制 MAPK 和 AKT 级联反应，对 PIK3CA 突变型 HCC 有效。此外，将 alpelisib 与 mTOR 或 CDK4/6 抑制剂联合使用对 PIK3CA 突变型 HCC 具有协同疗效，为 HCC 的精准医学提供了新的机会。
