Dual Targeting of Insulin Receptor and KIT in Imatinib-Resistant Gastrointestinal Stromal Tumors

Chen, Weicai; Kuang, Ye; Qiu, Haibo; Cao, Zhifa; Tu, Yuqing; Sheng, Qing; Eilers, Grant; He, Quan; Li, Hailong; Zhu, Mei‐Jun; Wang, Yuexiang; Zhang, Rongqing; Wu, Yugang; Meng, Fanyue; Fletcher, Jonathan A.; Ou, Wen‐Bin

doi:10.1158/0008-5472.can-17-0917

Cited by 28 publications

(21 citation statements)

References 43 publications

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“…41 Linsitinib has been proven to have antiproliferative effects in cell lines and xenograft models in a variety of cancers. 42,43 In our study, we observed that linsitinib treatment blocked the IGF-1-induced deacetylation of ENO2 and suppressed EMT, thereby inhibiting tumor growth and liver metastasis, indicating the potential clinical value of linsitinib in preventing liver metastasis in patients with deacetylated ENO2.…”

Section: Discussionmentioning

confidence: 60%

Insulin-like growth factor 1-induced enolase 2 deacetylation by HDAC3 promotes metastasis of pancreatic cancer

Zheng

Yang

et al. 2020

Sig Transduct Target Ther

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Enolase 2 (ENO2) is a key glycolytic enzyme in the metabolic process of glycolysis, but its potential function in pancreatic ductal adenocarcinoma (PDAC) is unclear. In this study, we observed a significant overexpression of ENO2 in PDAC tissues, and its expression was correlated with metastasis and poor prognosis in PDAC patients. K394 was identified as a major acetylation site in ENO2 that regulates its enzymatic activity, cell metabolism and PDAC progression. Knockdown of ENO2 suppressed tumor growth and liver metastasis in PDAC. Re-expression of wild-type (WT) ENO2, but not the K394 acetylation mimetic mutant, could reverse the decreased tumor malignancy. We further characterized histone deacetylase 3 (HDAC3) and P300/CBP-associated factor (PCAF) as the potential deacetylase and acetyltransferase for ENO2, respectively. HDAC3-mediated deacetylation was shown to lead to ENO2 activation and enhancement of glycolysis. Importantly, insulin-like growth factor-1 (IGF-1) was found to decrease K394 acetylation and stimulate ENO2 activity in a dose-and time-dependent manner. The PI3K/AKT/mTOR pathway facilitated the phosphorylation of HDAC3 on S424, which promoted K394 deacetylation and activation of ENO2. Linsitinib, an oral small-molecule inhibitor of IGF-1R, could inhibit IGF-1-induced ENO2 deacetylation by HDAC3 and the PI3K/AKT/mTOR pathway. Furthermore, linsitinib showed a different effect on the growth and metastasis of PDAC depending on the overexpression of WT versus K394mutant ENO2. Our results reveal a novel mechanism by which acetylation negatively regulates ENO2 activity in the metastasis of PDAC by modulating glycolysis. Blockade of IGF-1-induced ENO2 deacetylation represents a promising strategy to prevent the development of PDAC.

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Section: Discussionmentioning

confidence: 60%

Insulin-like growth factor 1-induced enolase 2 deacetylation by HDAC3 promotes metastasis of pancreatic cancer

Zheng

Yang

et al. 2020

Sig Transduct Target Ther

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“…Colony formation assays were performed as published previously with minor modifications [12]. In brief, GIST48B and PC-9 cells were plated at 5000 and 3,000 cells/well in 6-well plates, respectively, and cultured in RPMI 1640, for 6 days before treatment with gefitinib.…”

Section: Colony Formation Assaymentioning

confidence: 99%

“…Although KIT inhibition by imatinib represents a major therapeutic advance for patients with inoperable GIST, most patients eventually experience clinical progression due to multiple imatinib-resistant mechanisms, which include acquisition of secondary mutations in the KIT kinase domain [11,12], genomic amplification of KIT, and activation of alternate RTKs [2]. Approximately 10% of KIT-positive GISTs lose KIT expression at time of clinical progression during imatinib therapy [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Activated tyrosine kinases in gastrointestinal stromal tumor with loss of KIT oncoprotein expression

Zuo

et al. 2018

Cell Cycle

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Oncogenic KIT or PDGFRA receptor tyrosine kinase (TK) mutations are compelling therapeutic targets in gastrointestinal stromal tumors (GISTs), and the KIT/PDGFRA kinase inhibitor, imatinib, is the standard of care for patients with metastatic GIST. However, approximately 10% of KIT-positive GIST metastases lose KIT expression at the time of clinical progression during imatinib therapy. In the present report, we performed TK-activation screens, using phosphotyrosine-TK double immunoaffinity purification and mass spectrometry, in GIST in vitro models lacking KIT expression. These studies demonstrated tyrosinephosphorylated EGFR, AXL, and EPHA2 in four of six KIT-negative GIST lines (GIST62, GIST522, GIST54, GIST226, GIST48B, and GIST430B), and tyrosine-phosphorylated focal adhesion kinase (FAK) in each of the six KIT-negative lines. AXL expression was strong in KIT-negative or-weak clinical GIST samples that were obtained from progressing metastases during imatinib therapy. AXL knockdown inhibited viability in three KIT-negative GIST cell lines (GIST62, GIST54, and GIST522), but not in an AXL-negative, KITpositive GIST control cell line (GIST430). AXL inhibition by R428, a specific AXL kinase inhibitor, reduced viability in AXL-activated GIST54. AXL knockdown in GIST62, GIST522, and GIST54 was accompanied by an increase in p21, p27, and p53 expression. By contrast, gefitinib-mediated EGFR inhibition, PF562271mediated FAK inactivation, and shRNA-mediated knockdowns of EPHA2 and FAK had no effect on viability or colony formation of the KIT-negative GISTs. These findings highlight the potential relevance of AXL/p53 signaling as a therapeutic target in a subset of GISTs that have lost KIT oncoprotein expression.

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“…Aberrant signaling pathways are involved in carcinogenic processes, such as RTK and FAK-p53-MDM2 signaling. 52,53 Thus, molecular targeted inhibitors against these aberrant signals also may deliver a new combination strategy with oncolytic virotherapy for future PDAC treatment.…”

Section: Discussionmentioning

confidence: 99%

Oncolytic Adenovirus Expressing ST13 Increases Antitumor Effect of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Against Pancreatic Ductal Adenocarcinoma

Zhang

Huang

et al. 2020

Human Gene Therapy

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Oncolytic adenoviruses (OAds) are promising agents for cancer therapy, representing a novel therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC). However, there are challenges associated with the successful use of an OAd alone, involving the security of the viral vector and screening of an effective antitumor gene. In the present study, a novel OAd CD55-ST13-tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was constructed in which the dual therapeutic genes ST13 and TRAIL were inserted, featuring the carcinoembryonic antigen (CEA) as a promoter to control E1A and deletion of the 55 kDa E1B gene. ST13, known as a colorectal cancer suppressor gene, exhibited lower expression in PDAC than in tumor-adjacent tissues and was associated with poor prognosis in PDAC patients. In vitro studies demonstrated that CD55-ST13-TRAIL was effective in promoting the expression of ST13 and TRAIL in CEApositive pancreatic cancer cells. Moreover, CD55-ST13-TRAIL exhibited a synergistic effect toward tumor cell death compared with CD55-ST13 alone or CD55-TRAIL alone, and inhibited tumor cell proliferation and induced cell apoptosis dependent on caspase pathways in PDAC cells. Furthermore, xenograft experiments in a mouse model indicated that CD55-ST13-TRAIL significantly inhibited tumor growth and improved the survival of animals with xenografts. The findings demonstrate that oncolytic virotherapy under the control of the promoter CEA enables safe and efficient treatment of PDAC, and suggest that it represents a promising candidate for the treatment of metastatic diseases.

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Dual Targeting of Insulin Receptor and KIT in Imatinib-Resistant Gastrointestinal Stromal Tumors

Cited by 28 publications

References 43 publications

Insulin-like growth factor 1-induced enolase 2 deacetylation by HDAC3 promotes metastasis of pancreatic cancer

Insulin-like growth factor 1-induced enolase 2 deacetylation by HDAC3 promotes metastasis of pancreatic cancer

Activated tyrosine kinases in gastrointestinal stromal tumor with loss of KIT oncoprotein expression

Oncolytic Adenovirus Expressing ST13 Increases Antitumor Effect of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Against Pancreatic Ductal Adenocarcinoma

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