LMTK3 confers chemo-resistance in breast cancer

Stebbing, Justin; Shah, Kalpit; Lit, Lei Cheng; Gagliano, Teresa; Ditsiou, Angeliki; Wang, Tingting; Wendler, Franz; Simon, Thomas R.; Szabó, Krisztián; O’Hanlon, Timothy; Dean, Michael; Roslani, April Camilla; Cheah, Swee Hung; Lee, Soo‐Chin; Giamas, Georgios

doi:10.1038/s41388-018-0197-0

Cited by 36 publications

(42 citation statements)

References 68 publications

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“…The results showed higher LMTK3 expression was correlated with progression and poor prognosis in breast cancer [22]. Interestingly, LMTK3 also enhanced resistance to endocrine therapy in breast cancer by reducing autophagy [23] and confers chemoresistance in breast cancer by the formation of cH2AX foci [9]. It has also been reported that LMTK3 was an oncogene and a significant prognostic marker in colorectal cancer, lung cancer, gastric cancer, gastrointestinal stromal tumor and melanoma [24][25][26][27][28].…”

Section: Discussionmentioning

confidence: 99%

“…The pathogenetic role of LMTK3 in breast cancer has been confirmed by several studies [6][7][8]. LMTK3 promotes breast cancer progression and decreased the sensitivity to doxorubicin treatment by decreased activity of ataxia-telangiectasia mutated kinase [9]. Shi et al [10] found that expression of preoperative soluble LMTK3 (sLMTK3) is an independent prognostic factor for patients with colorectal cancer compared with patients with low levels of sLMTK3, and patients with high sLMTK3 expression showed a poorer overall survival.…”

Section: It Can Catalyze Protein Phosphorylation and Directly Ormentioning

confidence: 93%

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LMTK3 promotes tumorigenesis in bladder cancer via the ERK/MAPK pathway

Jiang

Yang

et al. 2020

FEBS Open Bio

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Lemur tyrosine kinase 3 (LMTK3) is a key member of the serine–threonine tyrosine kinase family. It plays an important role in breast cancer tumorigenesis and progression. However, its biological role in bladder cancer remains elusive. In this study, we demonstrated that LMTK3 was overexpressed in bladder cancer and was positively correlated with bladder cancer malignancy. High LMTK3 expression predicted poor overall survival. Knockdown of LMTK3 in bladder cancer cells triggered cell‐cycle arrest at G2/M phase, suppressed cell growth, and induced cell apoptosis in bladder cancer cells. Furthermore, Transwell assays revealed that reduction of LMTK3 decreased cell migration by regulating the epithelial‐to‐mesenchymal transition pathway. Conversely, LKTM3 overexpression was shown to promote proliferation and migration of bladder cancer cells. We assessed phosphorylation of MEK and ERK1/2 in bladder cancer cells depleted of LMTK3 and demonstrated a reduced phosphorylation status compared with the control group. Using an MAPK signaling‐specific inhibitor, U0126, we could rescue the promotion of proliferation and viability in LMTK3‐overexpressing cells. In conclusion, we extend the status of LMTK3 as an oncogene in bladder cancer and provide evidence for its function via the activation of the ERK/MAPK pathway. Thus, targeting LMTK3 may hold potential as a diagnostic and prognostic biomarker and as a possible future treatment for bladder cancer.

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Section: Discussionmentioning

confidence: 99%

Section: It Can Catalyze Protein Phosphorylation and Directly Ormentioning

confidence: 93%

LMTK3 promotes tumorigenesis in bladder cancer via the ERK/MAPK pathway

Jiang

Yang

et al. 2020

FEBS Open Bio

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“…With comprehensive profiling of CAL-101 mediated changes in the secretome of fibroblast cell lines established, next we investigated how these secreted proteins altered the transcriptional state of MDA-MB-231 cells. We cultured MDA-MB-231 in a transwell along with CAL-101 or vehicle-treated MRC5 cells for 24 hours and total RNA was extracted from MDA-MB-231 and processed as described earlier (36). As anticipated, whole transcriptome data showed a high degree of similarity between replicate samples and most significant variations between MDA-MB-231 cells co-cultured with CAL-101 treated or untreated MRC5 cells (Supplementary Figure 11).…”

Section: Integrated Secretome and Transcriptomic Analyses Reveal Fibrmentioning

confidence: 67%

“…Cell viability assay was performed as previously described (69) (36). Briefly, cells were seeded in 5.000 for well in a 96 well plate and treated with the indicated compound and time points and cell viability was evaluated by Cell Titer-Glo 2.0 (Promega) according to manufacturer instruction.…”

Section: Cell Viabilitymentioning

confidence: 99%

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Global kinome silencing combined with 3D invasion screening of the tumor microenvironment identifies fibroblast-expressed PIK3Cδ involvement in triple-negative breast cancer progression

Gagliano

Shah

Gargani

et al. 2019

Preprint

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As there is growing evidence for the tumor microenvironment's (TME) role in tumorigenesis, we sought to investigate the role of fibroblast-expressed kinases in triple negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3Cδ (f-PIK3Cδ) as a key regulator of progression. Although PIK3Cδ has been mainly described in leucocytes, we detected high expression in primary fibroblasts derived from TNBC patients, while PIK3Cδ was undetectable in cancer epithelial cell lines. Genetic and pharmacologic gain-and loss-of functions experiments verified the contribution of f-PIK3Cδ in TNBC cell invasion. By employing an integrated secretomics and transcriptomics analysis, we revealed a paracrine mechanism via which f-PIK3Cδ confers its pro-tumorigenic effects. Inhibition of f-PIK3Cδ promoted the secretion of factors, including PLGF and BDNF, which subsequently led to upregulation of NR4A1 in TNBC cells where it acts as a tumor suppressor. Inhibition of PIK3Cδ in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3Cδ in cancer progression. Similar results were observed in the MMTV-PyMT transgenic BC mouse model, in addition to a decrease on tumor metastasis emphasizing the potential immune-independent effects of PIK3Cδ inhibition. Finally, analysis of BC patient cohorts and TCGA datasets identified f-PIK3Cδ (protein and mRNA levels) as an independent prognostic factor for overall and disease free survival, highlighting it as a therapeutic target for TNBC.

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Kinome‐Wide Synthetic Lethal Screen Identifies PANK4 as a Modulator of Temozolomide Resistance in Glioblastoma

Vella,

Ditsiou,

Chalari

et al. 2024

Advanced Science

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Temozolomide (TMZ) represents the cornerstone of therapy for glioblastoma (GBM). However, acquisition of resistance limits its therapeutic potential. The human kinome is an undisputable source of druggable targets, still, current knowledge remains confined to a limited fraction of it, with a multitude of under‐investigated proteins yet to be characterized. Here, following a kinome‐wide RNAi screen, pantothenate kinase 4 (PANK4) isuncovered as a modulator of TMZ resistance in GBM. Validation of PANK4 across various TMZ‐resistant GBM cell models, patient‐derived GBM cell lines, tissue samples, as well as in vivo studies, corroborates the potential translational significance of these findings. Moreover, PANK4 expression is induced during TMZ treatment, and its expression is associated with a worse clinical outcome. Furthermore, a Tandem Mass Tag (TMT)‐based quantitative proteomic approach, reveals that PANK4 abrogation leads to a significant downregulation of a host of proteins with central roles in cellular detoxification and cellular response to oxidative stress. More specifically, as cells undergo genotoxic stress during TMZ exposure, PANK4 depletion represents a crucial event that can lead to accumulation of intracellular reactive oxygen species (ROS) and subsequent cell death. Collectively, a previously unreported role for PANK4 in mediating therapeutic resistance to TMZ in GBM is unveiled.

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LMTK3 confers chemo-resistance in breast cancer

Cited by 36 publications

References 68 publications

LMTK3 promotes tumorigenesis in bladder cancer via the ERK/MAPK pathway

LMTK3 promotes tumorigenesis in bladder cancer via the ERK/MAPK pathway

Global kinome silencing combined with 3D invasion screening of the tumor microenvironment identifies fibroblast-expressed PIK3Cδ involvement in triple-negative breast cancer progression

Kinome‐Wide Synthetic Lethal Screen Identifies PANK4 as a Modulator of Temozolomide Resistance in Glioblastoma

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