Rational combination of <scp>SHP2</scp> and <scp>mTOR</scp> inhibition for the treatment of hepatocellular carcinoma

Mulero‐Sánchez, Antonio; Ramirez, Christel; Chatinier, Aimée du; Wang, Hui; Koomen, Sofie J.I.; Song, Ji‐Ying; Groot, Marnix HP de; Lieftink, Cor; Bosma, Astrid; Burylo, Artur M; Tellingen, Olaf van; Beijersbergen, Roderick L.; Wang, Cun; Akkari, Leila; Bernards, René; Mainardi, Sara

doi:10.1002/1878-0261.13377

Cited by 5 publications

(3 citation statements)

References 63 publications

(90 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SHP2 inhibition decreases adaptive resistance to sorafenib by preventing the reactivation of the MEK/ERK and AKT signaling pathways induced by RTK, according to the findings of this study. In HCC, mTOR and SHP2 inhibition have been shown to have a similar synergistic impact ( 100 ).…”

Section: The Role Of Shp2 In Different Solid Tumor Entitiesmentioning

confidence: 99%

“…Combining PI3K and SHP2 inhibitors counteracts acquired and intrinsic breast cancer cell resistance to PI3K inhibition mediated by activated receptor tyrosine kinases ( 132 ). And in analogy, activation of multiple RTKs upon mTOR inhibition in HCC yields a highly synergistic effect of co-inhibition of both mTOR and SHP2 by triggering apoptosis ( 100 ).…”

Section: Shp2 and Therapy Resistance Of Solid Tumorsmentioning

confidence: 99%

See 1 more Smart Citation

Tyrosine phosphatase PTPN11/SHP2 in solid tumors - bull’s eye for targeted therapy?

Chen,

Keller,

Hafner

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

Encoded by PTPN11, the Src-homology 2 domain-containing phosphatase 2 (SHP2) integrates signals from various membrane-bound receptors such as receptor tyrosine kinases (RTKs), cytokine and integrin receptors and thereby promotes cell survival and proliferation. Activating mutations in the PTPN11 gene may trigger signaling pathways leading to the development of hematological malignancies, but are rarely found in solid tumors. Yet, aberrant SHP2 expression or activation has implications in the development, progression and metastasis of many solid tumor entities. SHP2 is involved in multiple signaling cascades, including the RAS-RAF-MEK-ERK-, PI3K-AKT-, JAK-STAT- and PD-L1/PD-1- pathways. Although not mutated, activation or functional requirement of SHP2 appears to play a relevant and context-dependent dichotomous role. This mostly tumor-promoting and infrequently tumor-suppressive role exists in many cancers such as gastrointestinal tumors, pancreatic, liver and lung cancer, gynecological entities, head and neck cancers, prostate cancer, glioblastoma and melanoma. Recent studies have identified SHP2 as a potential biomarker for the prognosis of some solid tumors. Based on promising preclinical work and the advent of orally available allosteric SHP2-inhibitors early clinical trials are currently investigating SHP2-directed approaches in various solid tumors, either as a single agent or in combination regimes. We here provide a brief overview of the molecular functions of SHP2 and collate current knowledge with regard to the significance of SHP2 expression and function in different solid tumor entities, including cells in their microenvironment, immune escape and therapy resistance. In the context of the present landscape of clinical trials with allosteric SHP2-inhibitors we discuss the multitude of opportunities but also limitations of a strategy targeting this non-receptor protein tyrosine phosphatase for treatment of solid tumors.

show abstract

Section: The Role Of Shp2 In Different Solid Tumor Entitiesmentioning

confidence: 99%

Section: Shp2 and Therapy Resistance Of Solid Tumorsmentioning

confidence: 99%

Tyrosine phosphatase PTPN11/SHP2 in solid tumors - bull’s eye for targeted therapy?

Chen,

Keller,

Hafner

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…In addition, it has been shown in preclinical models of small-cell lung cancer that the loss of the epigenetic modificatory KTMD2 activates ERBB2 and EGFR and that the combined inhibition of SHP2 and ERBB2 results in tumor regression ( 107 ). Moreover, SHP2 inhibition has been shown to be an effective combination strategy in hepatocellular carcinoma in combination with an mTOR inhibitor ( 108 ). The studies collectively show that the inhibition of SHP2 in cancer would represent a solid strategy to treat, prevent, and delay resistance mechanisms to currently available targeted therapies.…”

Section: Shp2: a Therapeutic Target In Cancermentioning

confidence: 99%

SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment

Sodir,

Pathria,

Adamkewicz

et al. 2023

Cancer Discovery

View full text Add to dashboard Cite

The protein phosphatase SHP2/PTPN11 has been reported to be a key modulator of proliferative pathways in a wide range of malignancies. Intriguingly, SHP2 has also been described as a critical regulator of the tumor microenvironment. Based on this evidence SHP2 is considered a multifaceted target in cancer, spurring the notion that the development of direct inhibitors of SHP2 would provide the twofold benefit of tumor intrinsic and extrinsic inhibition. In this review, we will discuss the role of SHP2 in cancer and the tumor microenvironment, and the clinical strategies in which SHP2 inhibitors are leveraged as combination agents to improve therapeutic response. Significance: The SHP2 phosphatase functions as a pleiotropic factor, and its inhibition not only hinders tumor growth but also reshapes the tumor microenvironment. Although their single-agent activity may be limited, SHP2 inhibitors hold the potential of being key combination agents to enhance the depth and the durability of tumor response to therapy.

show abstract

Therapeutic potential of targeting protein tyrosine phosphatases in liver diseases

Wang,

Zhang,

et al. 2024

Acta Pharmaceutica Sinica B

View full text Add to dashboard Cite

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

Cited by 5 publications

References 63 publications

Tyrosine phosphatase PTPN11/SHP2 in solid tumors - bull’s eye for targeted therapy?

Tyrosine phosphatase PTPN11/SHP2 in solid tumors - bull’s eye for targeted therapy?

SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment

Therapeutic potential of targeting protein tyrosine phosphatases in liver diseases

Contact Info

Product

Resources

About