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Alpelisib combination treatment as novel targeted therapy against hepatocellular carcinoma.

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机构： [1]Department of Liver Surgery, Center of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, Sichuan, China [2]Department of Bioengineering andTherapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA [3]Department of General Surgery, Affiliated Haixia Hospital of Huaqiao University, The 910Hospital, Quanzhou, Fujian, China [4]Department of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, China [5]Key Laboratory of Biorheological Science andTechnology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China [6]Institute of Pathology, University of Regensburg, Regensburg, Germany

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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.© 2021. The Author(s).

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出版当年[2021]版：

大类 | 1 区

生物学

小类 | 2 区细胞生物学

最新[2023]版：

大类 | 1 区

生物学

小类 | 2 区细胞生物学

第一作者：

第一作者机构： [1]Department of Liver Surgery, Center of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, Sichuan, China [2]Department of Bioengineering andTherapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA

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