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Alpelisib combination treatment as novel targeted therapy against hepatocellular carcinoma
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Alpelisib combination treatment as novel targeted therapy against hepatocellular carcinoma
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Journal Article
Alpelisib combination treatment as novel targeted therapy against hepatocellular carcinoma
2021
Overview
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.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ 13/109
/ 13/2
/ 82
/ 82/80
/ Animals
/ Benzoxazoles - therapeutic use
/ Biomedical and Life Sciences
/ Carcinoma, Hepatocellular - drug therapy
/ Carcinoma, Hepatocellular - genetics
/ Carcinoma, Hepatocellular - pathology
/ Class I Phosphatidylinositol 3-Kinases - genetics
/ Female
/ Humans
/ Liver Neoplasms - drug therapy
/ MAP Kinase Signaling System - drug effects
/ Mice
/ Piperazines - therapeutic use
/ Proto-Oncogene Proteins c-akt - metabolism
/ Proto-Oncogene Proteins c-met - genetics
/ PTEN Phosphohydrolase - metabolism
