Early Combined SHP2 Targeting Reverses the Therapeutic Resistance of Vemurafenib in Thyroid Cancer

Ma, Weike; Tian, Ming; Hu, Linfei; Ruan, Xianhui; Zhang, Wei; Zheng, Xiangqian; Gao, Ming

doi:10.7150/jca.83853

Cited by 3 publications

(11 citation statements)

References 52 publications

(64 reference statements)

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“…SHP2 blockade can overcome MEK inhibitor resistance, consistent with the findings of studies on other tumor types and leads to TC growth suppression that is persistent, particularly in differentiated thyroid carcinoma (DTC) cells (120). On the basis of these concepts, Ma et al (121) recently showed that vemurafenibinduced cancer sensitivity was enhanced by inhibiting SHP2, which also reversed the reactivation of the MAPK/ERK signaling cascade brought on by RTK activation.…”

Section: Thyroid Cancersupporting

confidence: 67%

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

Chen,

Keller,

Hafner

et al. 2024

Front. Immunol.

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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.

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Section: Thyroid Cancersupporting

confidence: 67%

“…On the basis of these concepts, Ma et al. ( 121 ) recently showed that vemurafenib-induced cancer sensitivity was enhanced by inhibiting SHP2, which also reversed the reactivation of the MAPK/ERK signaling cascade brought on by RTK activation.…”

Section: The Role Of Shp2 In Different Solid Tumor Entitiesmentioning

confidence: 99%

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

Chen,

Keller,

Hafner

et al. 2024

Front. Immunol.

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“…Several studies have raised the possible mechanisms of the resistance to BRAF inhibitors in BRAF-mutant thyroid cancers. For example, a previous study has evidenced that the reactivation of ERK signaling as a major effector of BRAF V600E mutation is strongly associated with compensatory activation of upstream RTKs [ 25 ]. For example, BRAF inhibitors promote the transcription of HER3 by releasing the transcription repressor CTBP from its promoter via the inhibition of ERK signaling.…”

Section: Discussionmentioning

confidence: 99%

Targeting NG2 relieves the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitors

Sui,

Wang,

Liu

et al. 2024

Cell. Mol. Life Sci.

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BRAFV600E represents a constitutively active onco-kinase and stands as the most prevalent genetic alteration in thyroid cancer. However, the clinical efficacy of small-molecule inhibitors targeting BRAFV600E is often limited by acquired resistance. Here, we find that nerve/glial antigen 2 (NG2), also known as chondroitin sulfate proteoglycan 4 (CSPG4), is up-regulated in thyroid cancers, and its expression is increased with tumor progression in a BRAFV600E-driven thyroid cancer mouse model. Functional studies show that NG2 knockout almost does not affect tumor growth, but significantly improves the response of BRAF-mutant thyroid cancer cells to BRAF inhibitor PLX4720. Mechanistically, the blockade of ERK-dependent feedback by BRAF inhibitor can activate receptor tyrosine kinase (RTK) signaling, causing the resistance to this inhibitor. NG2 knockout attenuates the PLX4720-mediated feedback activation of several RTKs, improving the sensitivity of BRAF-mutant thyroid cancer cells to this inhibitor. Based on this finding, we propose and demonstrate an alternative strategy for targeting NG2 to effectively treat BRAF-mutant thyroid cancers by combining multiple kinase inhibitor (MKI) Sorafenib or Lenvatinib with PLX4720. Thus, this study uncovers a new mechanism in which NG2 contributes to the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitor, and provides a promising therapeutic option for BRAF-mutant thyroid cancers.

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“…In addition, bevacizumab inhibited the pro-invasive properties of dabrafenib in these cells [173]. Vemurafenib-treated BRAF mutant thyroid cancer cells also showed an upregulation of VEGFR2 associated with SHP2 activation [100]. Suppression of miR-126-3p also contributed to dabrafenib resistance in BRAF mutant melanoma by upregulating VEGF-A and ADAM9 (a disintegrin and metalloproteinase domain 9) (Figure 2b) [174].…”

Section: Additional Mechanisms and Factors Of Vegfr-mediated Braf Inh...mentioning

confidence: 98%

“…Several RTKs, including EGFR, were upregulated in BRAF mutant thyroid cancers dependent on phosphatase SHP2 (protein tyrosine phosphatase 2, a downstream factor of RTK signaling). Inhibition of SHP2 either by knockdown or by the SHP2 inhibitor SHP099 reversed late resistance to vemurafenib in BRAF mutant thyroid cancer cells by decelerating MAPK/ERK reactivation (Figure 2a) [100]. The phosphatase PTEN (phosphatase and tensin homolog) hydrolyzes phosphatidyl-inositol triphosphate PIP 3 , the activator of PI3K, to PIP 2 , thereby suppressing PI3K/AKT signaling.…”

Section: Additional Mechanisms and Factors Of Egfr-mediated Braf Inhi...mentioning

confidence: 99%

Role and Function of Receptor Tyrosine Kinases in BRAF Mutant Cancers

Biersack,

Tahtamouni,

Höpfner

2024

Receptors

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The development of potent BRAF inhibitors has revolutionized the treatment of BRAF mutant cancers, in particular, melanomas. However, BRAF mutant cancers of other entities, e.g., colorectal cancers, display distinctly reduced responses to BRAF inhibitors. In addition, the emergence of cancer resistance to BRAF inhibitor treatment poses a severe problem. The reactivation of MAPK/ERK signaling was identified as an important mode of BRAF inhibitor resistance. Receptor tyrosine kinases (RTKs), which are prominent anticancer drug targets in their own right, play a crucial role in the development of drug resistance to BRAF inhibitors and the reactivation of MAPK/ERK signal transduction, as well as the establishment of bypassing signaling pathways. MAPK reactivation can occur via increased expression of RTKs, altered RTK signaling, and post-translational processes, among others. This review summarizes the influence of pertinent RTKs on BRAF mutant cancers and BRAF inhibitor resistance and outlines possible and proven ways to circumvent BRAF-associated resistance mechanisms.

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Early Combined SHP2 Targeting Reverses the Therapeutic Resistance of Vemurafenib in Thyroid Cancer

Cited by 3 publications

References 52 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?

Targeting NG2 relieves the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitors

Role and Function of Receptor Tyrosine Kinases in BRAF Mutant Cancers

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