Rational combination of SHP2 and mTOR inhibition for the treatment of hepatocellular carcinoma.

Autor: Mulero-Sánchez A; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Ramirez CFA; Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., du Chatinier A; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Wang H; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, China., Koomen SJI; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Song JY; Department of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., de Groot MHP; Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Lieftink C; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Bosma A; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Burylo A; Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., van Tellingen O; Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Beijersbergen RL; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Wang C; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, China., Akkari L; Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Bernards R; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, China., Mainardi S; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2023 Jun; Vol. 17 (6), pp. 964-980. Date of Electronic Publication: 2023 Feb 09.
DOI: 10.1002/1878-0261.13377
Abstrakt: Liver cancer is the fourth most common cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the main primary malignancy affecting the liver. Unfortunately, there are still limited therapeutic options for HCC, and even the latest advances have only increased the overall survival modestly. Thus, new treatment strategies and rational drug combinations are urgently needed. Reactivation of receptor tyrosine kinases (RTK) has been described as a mechanism of intrinsic resistance to targeted therapies in a variety of cancers, including inhibitors of mTOR. The design of rational combination therapies to overcome this type of resistance is complicated by the notion that multiple RTK can be upregulated during the acquisition of resistance. SHP2, encoded by the gene PTPN11, acts downstream of virtually all RTK, and has proven to be a good target for small molecule inhibitors. Here, we report activation of multiple RTK upon mTOR inhibition in HCC which, through SHP2, leads to reactivation of the mTOR pathway. We show that co-inhibition of both mTOR and SHP2 is highly synergistic in vitro by triggering apoptosis. More importantly, the combination is well-tolerated and outperforms the monotherapies in impairing tumor growth in multiple HCC mouse models. Our findings suggest a novel rational combination therapy for the treatment of HCC.
(© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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