Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is currently ranked as the sixth most common primary cancer and the fourth leading cause of cancer-related deaths worldwide [1]
These data indicate that mutations, alpelisib treatment did not improve the overall survival PIK3CA mutations could be identified in ~3% human HCCs; rate (Supplementary Fig. S8b)
We investigated the therapeutic potency of alpelisib in PIK3CA-mutated HCCs, either alone or in combination, using both in vitro and in vivo models
Summary
Hepatocellular carcinoma (HCC) is currently ranked as the sixth most common primary cancer and the fourth leading cause of cancer-related deaths worldwide [1]. A multi-kinase inhibitor, has been the first-line treatment drug for HCC in the past decade, but it has limited efficacy [2]. Additional multikinase inhibitors, including cabozantinib and regorafenib, have been approved for HCC treatment [3]. Immunotherapy has demonstrated significant therapeutic efficacy against advanced HCC, and it has become the first-line treatment option for advanced HCC [4]. Most patients eventually progress with all these therapies. Despite all this progress, tumor genetics-specific-targeted therapies against HCC are unsatisfactory. The development of novel treatment strategies against HCC, especially biomarker-based targeted therapies, is imperative
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