Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

Abstract

Background Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR) is one of the most effective single-drug systemic therapy against advanced HCC, but the identification of novel combination regimens for a continued improvement in overall survival is a big challenge. Recent studies highlighted the crucial role of focal adhesion kinase (FAK) in HCC growth. The aim of this study was to investigate the antitumor effects of three different FAK inhibitors (FAKi), alone or in combination with SOR, using in vitro and in vivo models of HCC. Methods The effect of PND1186, PF431396, TAE226 on cell viability was compared to SOR. Among them TAE226, emerging as the most effective FAKi, was tested alone or in combination with SOR using 2D/3D human HCC cell line cultures and HCC xenograft murine models. The mechanisms of action were assessed by gene/protein expression and imaging approaches, combined with high-throughput methods. Results TAE226 was the more effective FAKi to be combined with SOR against HCC. Combined TAE226 and SOR treatment reduced HCC growth both in vitro and in vivo by affecting tumour-promoting gene expression and inducing epigenetic changes via dysregulation of FAK nuclear interactome. We characterized a novel nuclear functional interaction between FAK and the NuRD complex. TAE226-mediated FAK depletion and SOR-promoted MAPK down-modulation caused a decrease in the nuclear amount of HDAC1/2 and a consequent increase of the histone H3 lysine 27 acetylation, thus counteracting histone H3 lysine 27 trimethylation. Conclusions Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduces HCC growth in vitro and in vivo. Also, our data highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising targets for HCC therapy.

Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2

“…TAE226 also inhibits tumor metastasis in breast cancer and Ewing sarcoma 37 , 38 . A recent study shows that combined TAE226 and sorafenib treatment reduce HCC growth in vitro and in vivo by affecting tumor-promoting gene expression and inducing epigenetic changes 25 . These studies indicate that TAE226 has antitumor effects and has potential application in cancer treatment.…”

“…Knockdown of PTK2 in HCC cells reduces in vitro and in vivo tumorigenicity by inducing G2/M arrest and apoptosis, decreasing anchorage-independent growth, and modulating the expression of cancer-promoting genes 24 . Combined PTK2 inhibitor and sorafenib reduce HCC growth by affecting tumor-promoting gene expression and inducing epigenetic changes 25 . PTK2 may be a novel prognostic biomarker for HCC recurrence and a potential therapeutic target for human HCC treatment.…”

New Insights on the Nuclear Functions and Targeting of FAK in Cancer

“…Over the last ten years, in addition to this kinase-dependent function, an unexpected kinase-independent role in the scaffolding and regulation of gene transcription was also discovered for FAK (ref. [4] and reviewed in [5,6]).…”

Integrated Multi-Omics Data Analysis Reveals Associations Between Glycosylation and Stemness in Hepatocellular Carcinoma

“…Surgical resection of HCC followed by chemotherapy is an ideal curative treatment strategy, but it is limited by advanced stage and metastasized tumor cells. While several new therapeutic agents, including checkpoint or tyrosine kinase inhibitors, have been approved by the FDA for patients who cannot undergo surgery or transplantation, their efficacy is unsatisfactory ( 3 , 4 ), and HCC patients still have an average survival of only 6 months ( 5 , 6 ). Liver cancer stem cells (LCSCs) are closely associated with the poor prognosis of HCC because they have more robust metastatic and tumorigenic properties than non-LCSCs.…”