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

ABSTRACT: 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.

SUBMITTER: Mulero-Sanchez A

PROVIDER: S-EPMC10257427 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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

Mulero-Sánchez Antonio A Ramirez Christel F A CFA du Chatinier Aimée A Wang Hui H Koomen Sofie J I SJI Song Ji-Ying JY de Groot Marnix H P MHP Lieftink Cor C Bosma Astrid A Burylo Artur A van Tellingen Olaf O Beijersbergen Roderick L RL Wang Cun C Akkari Leila L Bernards René R Mainardi Sara S

Molecular oncology 20230209 6

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 res ...[more]

PMID: 36650715

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Project description:BackgroundHepatocellular carcinoma (HCC) remains difficult to treat due to limited effective treatment options. While the proteasome inhibitor bortezomib has shown promising preclinical activity in HCC, clinical trials of bortezomib showed no advantage over the standard-of-care treatment sorafenib, highlighting the need for more clinically relevant therapeutic strategies. Here, we propose that rational drug combination design and validation in patient-derived HCC avatar models such as patient-derived xenografts (PDXs) and organoids can improve proteasome inhibitor-based therapeutic efficacy and clinical potential.MethodsHCC PDXs and the corresponding PDX-derived organoids (PDXOs) were generated from primary patient samples for drug screening and efficacy studies. To identify effective proteasome inhibitor-based drug combinations, we applied a hybrid experimental-computational approach, Quadratic Phenotypic Optimization Platform (QPOP) on a pool of nine drugs comprising proteasome inhibitors, kinase inhibitors and chemotherapy agents. QPOP utilizes small experimental drug response datasets to accurately identify globally optimal drug combinations.ResultsPreliminary drug screening highlighted the increased susceptibility of HCC PDXOs towards proteasome inhibitors. Through QPOP, the combination of second-generation proteasome inhibitor ixazomib (Ixa) and CDK inhibitor dinaciclib (Dina) was identified to be effective against HCC. In vitro and in vivo studies demonstrated the synergistic pro-apoptotic and anti-proliferative activity of Ixa + Dina against HCC PDXs and PDXOs. Furthermore, Ixa + Dina outperformed sorafenib in mitigating tumor formation in mice. Mechanistically, increased activation of JNK signaling mediates the combined anti-tumor effects of Ixa + Dina in HCC tumor cells.ConclusionsRational drug combination design in patient-derived avatars highlights the therapeutic potential of proteasome and CDK inhibitors and represents a feasible approach towards developing more clinically relevant treatment strategies for HCC.

Dataset Information

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

Publications

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

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