Lemur tyrosine kinase-3 (LMTK3) induces chemoresistance to cetuximab in colorectal cancer via the ERK/MAPK pathway

Wang, Cheng; Yang, Miaomiao; Gu, Xi; Gu, Yan‐Jing

doi:10.1080/21655979.2021.1974655

Cited by 6 publications

(3 citation statements)

References 40 publications

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“…Te reason for this phenomenon might be due to the heterogeneity in diferent breast cancer subtypes. Lemur tyrosine kinase 3(LMTK3) is an oncogenic receptor tyrosine kinase (RTK) implicated in various types of cancers, including breast, gastric, and colorectal cancer and melanoma [32][33][34][35]. KRAB-associated protein 1 (KAP1) binding to LMTK3.…”

Section: Discussionmentioning

confidence: 99%

Development and Verification of a Prognostic Stemness-Related Gene Signature in Triple-Negative Breast Cancer

Tan

Gao

et al. 2023

Journal of Oncology

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Background. It is well known that cancer stem cells can induce cancer metastasis, which causes the majority of cancer-related death, especially in triple-negative breast cancer (TNBC). TNBC features a high metastatic rate and low metastasis-free survival and is regarded as the most malignant subtype of breast cancer. The purpose of this study is to explore prognostic biomarkers that can predict metastasis of triple-negative breast cancer. Methods. The human triple-negative breast cancerSUM149PT cells were used for the study. The cancer stem cell spheres (sum149-Stem) and paired adherent cancer cells (sum149-Tumor) were collected to extract total RNAs. RNA-seq was used to analysis the mRNA expression of cancer stem cells and paired adherent cancer cells. Two different gene expression omnibus datasets (https://www.ncbi.nlm.nih.gov/gds), GSE58812 and GSE33926, were used to explore the mechanism of different expression genes between stem cells and adherent cancer cells. Seven genes showed prognostic function in all datasets. The STITCH database (https://www.stitchdata.com/) was used to explore the possible metastasis-inhibiting drugs that can target the seven genes. Each gene expression was compared by Pearson analysis. The receiver operating characteristic curve (ROC) and Kaplan–Meier survival curve were performed to assess the metastasis prognostic ability of the seven-gene modeling two different GEO datasets. Results. A subset of 7 stemness-related genes (SRGs) containing UCN, ST3GAL5, FDPS, HK2, MALL, LMTK3, and CRHR2 were identified in three independent cohorts. Univariate Cox analysis showed that ST3GAL5 plays an antitumor role in TNBC metastasis, and the other 6 genes promote the metastatic progression of TNBC. The ability of the 7-SRGs gene Cox model to predict TNBC metastasis was constructed with the GSE58812 dataset. Most of the genes showed significant expression in patients with different risk levels. Additionally, the model showed predictive value in another GEO dataset of TNBC patients. ROC curves indicated that the seven-gene model has a significant predictive value of TNBC metastasis. Conclusions. Expression analysis of the 7-SRGs signature model at diagnosis has predictive value for metastasis in TNBC patients.

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Section: Discussionmentioning

confidence: 99%

Development and Verification of a Prognostic Stemness-Related Gene Signature in Triple-Negative Breast Cancer

Tan

Gao

et al. 2023

Journal of Oncology

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“…Follow-up studies have further supported that elevated levels of LMTK3 in BC are associated with poorer overall survival (OS) and disease-free survival (DFS) [12]. Moreover, LMTK3 has also been implicated in endocrine [13] and chemotherapy resistance in BC [14], while us and others have described an involvement of LMTK3 in different signaling pathways [13,23].…”

Section: Introductionmentioning

confidence: 93%

The Inhibitory Properties of a Novel, Selective LMTK3 Kinase Inhibitor

Agnarelli

Betrán

Papakyriakou

et al. 2023

IJMS

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Recently, the oncogenic role of lemur tyrosine kinase 3 (LMTK3) has been well established in different tumor types, highlighting it as a viable therapeutic target. In the present study, using in vitro and cell-based assays coupled with biophysical analyses, we identify a highly selective small molecule LMTK3 inhibitor, namely C36. Biochemical/biophysical and cellular studies revealed that C36 displays a high in vitro selectivity profile and provides notable therapeutic effect when tested in the National Cancer Institute (NCI)-60 cancer cell line panel. We also report the binding affinity between LMTK3 and C36 as demonstrated via microscale thermophoresis (MST). In addition, C36 exhibits a mixed-type inhibition against LMTK3, consistent with the inhibitor overlapping with both the adenosine 5′-triphosphate (ATP)- and substrate-binding sites. Treatment of different breast cancer cell lines with C36 led to decreased proliferation and increased apoptosis, further reinforcing the prospective value of LMTK3 inhibitors for cancer therapy.

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“…Specifically, ERK1/2 is a major regulator of cell survival and one of the main effector downstream targets of EGFR. In colorectal cancer cells, cetuximab induces cell death in an ERK-dependent manner [ 47 , 48 ], and enhanced ERK1/2 activity is a possible mechanism of cetuximab resistance in head and neck squamous cell carcinoma and colorectal cancer cells [ 49 , 50 ]. Hence, we measured the ERK1/2 kinase activity of treated cells.…”

Section: Introductionmentioning

confidence: 99%

Human Blood Serum Can Diminish EGFR-Targeted Inhibition of Squamous Carcinoma Cell Growth through Reactivation of MAPK and EGFR Pathways

Kamashev

Shaban

Lebedev

et al. 2023

Cells

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Regardless of the presence or absence of specific diagnostic mutations, many cancer patients fail to respond to EGFR-targeted therapeutics, and a personalized approach is needed to identify putative (non)responders. We found previously that human peripheral blood and EGF can modulate the activities of EGFR-specific drugs on inhibiting clonogenity in model EGFR-positive A431 squamous carcinoma cells. Here, we report that human serum can dramatically abolish the cell growth rate inhibition by EGFR-specific drugs cetuximab and erlotinib. We show that this phenomenon is linked with derepression of drug-induced G1S cell cycle transition arrest. Furthermore, A431 cell growth inhibition by cetuximab, erlotinib, and EGF correlates with a decreased activity of ERK1/2 proteins. In turn, the EGF- and human serum-mediated rescue of drug-treated A431 cells restores ERK1/2 activity in functional tests. RNA sequencing revealed 1271 and 1566 differentially expressed genes (DEGs) in the presence of cetuximab and erlotinib, respectively. Erlotinib- and cetuximab-specific DEGs significantly overlapped. Interestingly, the expression of 100% and 75% of these DEGs restores to the no-drug level when EGF or a mixed human serum sample, respectively, is added along with cetuximab. In the case of erlotinib, EGF and human serum restore the expression of 39% and 83% of DEGs, respectively. We further assessed differential molecular pathway activation levels and propose that EGF/human serum-mediated A431 resistance to EGFR drugs can be largely explained by reactivation of the MAPK signaling cascade.

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Lemur tyrosine kinase-3 (LMTK3) induces chemoresistance to cetuximab in colorectal cancer via the ERK/MAPK pathway

Cited by 6 publications

References 40 publications

Development and Verification of a Prognostic Stemness-Related Gene Signature in Triple-Negative Breast Cancer

Development and Verification of a Prognostic Stemness-Related Gene Signature in Triple-Negative Breast Cancer

The Inhibitory Properties of a Novel, Selective LMTK3 Kinase Inhibitor

Human Blood Serum Can Diminish EGFR-Targeted Inhibition of Squamous Carcinoma Cell Growth through Reactivation of MAPK and EGFR Pathways

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